selective inhibitors of arginine methyltransferase 5 (prmt5)

专利摘要:
Disclosure is directed to Formula I compounds(Formula I)Also described are pharmaceutical compositions comprising compounds of Formula I, as well as methods of use and preparation.
公开号:BR112020002736A2
申请号:R112020002736-7
申请日:2018-08-09
公开日:2020-07-28
发明作者:Juan Luengo；Hong Lin；Rupa Shetty；Michael Hawkins
申请人:Prelude Therapeutics, Incorporated；
IPC主号:

专利说明:

[0001] [0001] This application claims priority benefit to US Provisional Patent Application No. 62 / 543,141, filed on August 9, 2017, US Provisional Patent Application No. 62/630,581, filed on February 14, 2018 and US Provisional Patent Application. 62 / 664,442, deposited on April 30,
[0002] [0002] The disclosure is directed to PRMT5 inhibitors and methods of using them. TECHNICAL STATUS
[0003] [0003] Protein arginine methylation is a common post-translational modification that regulates numerous cellular processes, including gene transcription, mMRNA splicing, DNA repair, cell protein localization, cell destiny determination and signaling. There are three types of methyl arginine species: WÂWNG monomethylarginine (MMA), WÂwNG, NG asymmetric dimethylarginine (ADMA) and WNG, symmetric dimethylarginine NG (SDMA). The formation of methylated arginines is catalyzed by the family of methyltransferases from the protein arginine methyl transferases (PRMTs). There are currently nine PRMTs noted in the human genome. Most of these enzymes are enzymes of the type | (PRMT1, -2, -3, -4, -6, -8) capable of mono- and asymmetric dimethylation of arginine, with S-adenosylmethionine (SAM) as methyl donor. PRMT-5, -7 and -9 are considered Type II enzymes that catalyze the symmetric dimethylation of arginines. Each PRMT species houses the characteristic motifs of seven beta-tape methyltransferases (Katz et al., 2003), as well as additional "double E" and "THW" sequence motifs, specific to the PRMT subfamily.
[0004] [0004] PRMT5 is like a general transcriptional repressor that works with various transcription factors and repressor complexes, including BRG1 and hBRM, Blimpl and Snail. This enzyme, once recruited to a promoter, symmetrically dimethyl H3R8 and H4R3. It is important to note that the H4R3 site is one of the main targets of PRMT1 methylation (ADMA) and is generally considered to be a transcriptional activation marker. Thus, the brands H4R3me2s (repressive; me2s indicate modification of SDMA) and H4R3me2a (active; me2a indicates modification of ADMA) are produced in vivo. The specificity of PRMT5 for H3R8 and H4R3 can be altered by its interaction with COPR5 and this may perhaps play an important role in determining the status of the PRMTS5 corepressor.
[0005] [0005] The aberrant expression of PRMTs has been identified in human cancers, and PRMTs are considered therapeutic targets. The global analysis of histone modifications in prostate cancer showed that histone H4R3 dimethylation is positively correlated with the increase in degree, and these changes are predictive of clinical outcomes.
[0006] [0006] PRMTS5 levels have been shown to be elevated in a panel of lymphoid cancer cell lines, as well as in clinical samples of mantle cell lymphoma. PRMTS5 interacts with various substrates involved in a variety of cellular processes, including RNA processing, signal transduction and regulation of transcription. PRMT5 can directly modify histone H3 and H4, resulting in the repression of gene expression. Overexpression of PRMT5 can stimulate cell growth and induce transformation by directly suppressing tumor suppressor genes. Pal et al., Mol. Cell. Biol. 2003, 7475; Pal et al. Mol. Cell. Biol. 2004, 9630; Wang et al. Mol. Cell. Biol. 2008, 6262; Chung et al. | Biol Chem 2013, 5534. In addition to its well-documented oncogenic functions in transcription and translation, the MYC transcription factor also protects adequate pre-messenger RNA splicing as an essential step in lymphomagenesis. Koh et al. Nature 2015, 523 7558; Hsu et al. Nature 2015 525, 384.
[0007] [0007] The discovery of cancer addictions has the potential to inform therapeutic strategies and identify possible drug targets. Integrating data from a comprehensive genomic profile of cancer cell lines and from the functional characterization of cancer cell dependencies, it was recently discovered that the loss of the enzyme methyltivadenosine phosphorylase (MTAP) confers a selective dependence on the protein arginine methyltransferase 5 (PRMTS5) and its WDR77 liaison partner. MTAP is often lost due to its proximity to the usually deleted tumor suppressor gene, CDKN2A. Cells that harbor MTAP deletions have increased intracellular concentrations of methylticadenosine (MTA, the metabolite cleaved by MTAP). In addition, MTA specifically inhibits the enzymatic activity of PRMTS5. Administration of either MTA or a small molecule PRMT5 inhibitor shows preferential impairment of cell viability for null cancer cell lines in MTAP, compared to isogenic counterparts expressing MTAP. Taken together, these findings reveal PRMT5 as a potential vulnerability in several cancer strains, augmented by a common "passenger" genomic alteration.
[0008] [0008] The developmental change in the human globin gene subtype from fetal to adult that begins at birth heralds the onset of hemoglobinopathies, b-thalassemia and sickle cell disease (SCD). The observation that increased expression of the adult globin gene (in the setting of the hereditary persistence of fetal hemoglobin [HPFH] mutations) significantly improves the clinical severity of thalassemia and SCD has led to the search for therapeutic strategies to reverse gene silencing gamma globin. The central point in the silencing of gamma genes is DNA methylation, which marks the critical CpG dinucleotides that flank the gene transcription starting site in erythroid cells in the adult bone marrow. These marks have been shown to be established as a consequence of the recruitment of DNA methyltransferase, DNMT3A to the gamma promoter by the protein arginine methyltransferase PRMT5. Zhao et al. Nat Struct Mol Biol. 2009 16, 304. PRMT5-mediated histone methylation H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing.
[0009] [0009] PRMTS5 induces the repressive histone tag, H4R3me2s, which serves as a model for direct binding of DNMT3A and subsequent DNA methylation. Loss of PRMTS5 binding or enzyme activity leads to the demethylation of CpG dinucleotides and activation of the gene. In addition to the H4R3me2s tag and DNA methylation, the binding of PRMT5 to the gamma promoter and its enzymatic activity are essential for the assembly of a multiprotein complex in the gamma promoter, which induces a series of coordinated repressive epigenetic marks. The disruption of this complex leads to reactivation of the expression of the gamma gene. These studies provide the basis for the development of PRMT5 inhibitors as target therapies for thalassemia and SCD. SUMMARY
[0010] [0010] Disclosure is directed to compounds of Formula |:
[0011] [0011] Stereoisomers of compounds of Formula | and their pharmaceutical salts and solvates are also described. Methods of using compounds of Formula | are described, as well as pharmaceutical compositions, including compounds of Formula | DETAILED DESCRIPTION OF ILLUSTRATIVE MODALITIES
[0012] [0012] Disclosure can be appreciated more fully by reference to the description below, including the following definitions and examples. Certain characteristics of the disclosed compositions and methods that are described by in the context of separate aspects, can also be provided in combination in a single aspect. Alternatively, various characteristics of the disclosed compositions and methods that are, for the sake of brevity, described in the context of a single aspect, can also be provided separately or in any subcombination.
[0013] [0013] The term "alkyl", when used alone or as part of a substituent group, refers to a group of straight or branched chain hydrocarbons having 1 to 12 carbon atoms ("C1-C12"), preferably 1 to 6 carbon atoms (“C1-Cç65”), in the group. Examples of alkyl groups include methyl (Me, Cialkyl), ethyl (Et, Cralkyl), N-propyl (C3alkyl), isopropyl (C3alkyl), butyl (Caalkyl), isobutyl (Caalkyl), sec-butyl (Caalkyl), tert- butyl (Caalquila), pentila (Csalquila), isopentyl (Csalquila), tert-pentyl (Csalquila), hexyl (Cçalquila), isohexyl (Cealquila), and the like.
[0014] [0014] The term "halo" when used alone or as part of a substituent group refers to chlorine, fluorine, bromine or iodine.
[0015] [0015] The term "haloalkyl" when used alone or as part of a substituent group refers to an alkyl group in which one or more hydrogen atoms have been replaced by one or more halogen atoms. Halogen atoms include chlorine, fluorine, bromine and iodine. Examples of the haloalkyl groups of the disclosure include, for example, trifluoromethyl (-CF3), chloromethyl (-CH2CI), and the like.
[0016] [0016] The term "cycloalkyl" when used alone or as part of a substituent group refers to groups of cyclic hydrocarbons containing, non-aromatic having 3 to 10 carbon atoms ("C3.C10"), preferably 3 to 6 carbon atoms (“C3.C6É”). Examples of cycloalkyl groups include, for example, cyclopropyl (C3) cyclobutyl (Ca), cyclopropylmethyl (Ca), cyclopentyl (Cs), cyclohexyl (Cs), 1-methylcyclopropyl (Ca), 2-methylcyclopentyl (Ca), adamantanyl (C10 ), and the like.
[0017] [0017] The term "heterocycloalkyl" when used alone or as part of a substituent group refers to any saturated monocyclic or bicyclic ring structure, from three to ten members, containing at least one heteroatom selected from the group consisting of O, N and S. The heterocycloalkyl group can be attached to any heteroatom or carbon atom in the ring, so that the result is a stable structure. Examples of suitable heterocycloalkyl groups include, but are not limited to, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxamine, and oxazepan.
[0018] [0018] The term "alkenyl" when used alone or as part of a substituent group refers to a straight or branched chain group having 2 to 12 carbon atoms ("C2.C12"), preferably 2 to 4 carbon atoms carbon (“C2-C4”) in the group, where the group includes at least one carbon-carbon double bond. Examples of alkenyl groups include vinyl (-CH = CH>; Coalkenyl) alla (-CH-CH = CH ;; C3alkenyl)) propenyl (-CH = CHCH; 3; Czalkenyl); isopropenyl (-C (CH3) = CH> 2; C3alkenyl), butenyl -CH = CHCH3CH3; Caalkenyl), sec-butenyl (-C (CH3) = CHCH3; Caalkenyl), iso-butenyl (-
[0019] [0019] The term "alkynyl" when used alone or as part of a substituent group refers to a straight or branched chain group having 2 to 12 carbon atoms ("C17.C127"), preferably 1 to 4 atoms carbon (“C1-C4”) in the group, where the group includes at least one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl (-C = CH; Coalquinyl); propargyl -CH2-C = CH; C3 alkynyl), propynyl -C = CCH3; C3zalquinyl); butynyl -C = CCH2CH3; Caalquinyl), pentinyl (CECCHCH2CH3; Csalquinyl), and the like.
[0020] [0020] The term "aryl" when used alone or as part of a substituent group refers to a mono- or bicyclic-aromatic hydrocarbon ring structure with 6 or 10 carbon atoms in the ring, where one or more carbon atoms carbon in the ring is optionally substituted by a halogen atom, a -C1-C3 alkyl group, an amine-substituted -C1-C3 alkyl group, a C1-C3haloalkyl group, an amino group (i.e., -NH2) or a group substituted amine. The term "aryl" when used alone or as part of a substituent group refers to a mono- or bicyclic-aromatic hydrocarbon ring structure with 6 or 10 ring carbon atoms, where one or more ring carbon atoms is optionally substituted with a halogen atom, a -C1-C3 alkyl group, an amine-substituted -C1-C3 alkyl group, an alkylamino-substituted -C1-C3 alkyl group, a hydroxy-substituted -C1-C3 alkyl group, a C1-C3haloalkyl group, an -O-C1- C3haloalkyl group, an amine group (i.e., -NH2), or a substituted amine group. Halogen atoms include chlorine, fluorine, bromine and iodine. Anine-substituted -C1-C3 alkyl groups include -CH2-NH2, -CH2CH2-NH> 2 groups, and the like. The alkylamino-substituted -C-Czalkyl groups include -CH3-NHCH; 3 groups and the like. C1-C3haloalkyl groups include, for example, -CF3, -CH2CF3 and the like. Amine-substituted groups include, for example, -NH-C (O) - NH7. The hydroxy substituted -C; 7-C3 alkyl groups include -CH,; - OH and the like. The term "aryl" also includes a mono- or bicyclic-aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, where two adjacent carbon atoms in the ring are optionally substituted so that said two carbon atoms adjacent substances and their respective substituents form a heterocyclic ring. Thus, aryl groups include, for example, 2,3-dihydrobenzofuran and 1,3-benzodioxolyl. Examples of aryl groups (substituted and unsubstituted) include phenyl, aminomethylphenyl, 3- (aminomethyl) phenyl, phenylurea, methylchlorophenyl, 3-methyl-4-chlorophenyl, fluorochlorophenyl, 3-fluoro-4-chlorophenyl, naphthyl, fluorophenyl, trifluoromethyl, trifluoromethyl, 4-trifluoromethylphenyl, fluoro-trifluoromethylphenyl, - 3-fluoro-4-trifluoromethylphenyl, - 4-fluoro-3-trifluoromethylphenyl, difluorophenyl, 3,4-difluorophenyl, chlorophenyl, 4-chlorophenyl, 4-chloro-2- (aminomethyl) -4-chlorophenyl, 4-chloro-2 - ((methylamino) methyl) phenyl, dichlorophenyl, a 3, 4-dichlorophenyl, - bromophenyl, - iodophenyl, - chlorofluorophenyl, - fluoronaftila, difluoronaphthalyl, bromonaphile , 4-isopropylphenyl, 4- (trifluoromethoxy) phenyl, benzo [d] [1,3] dioxolyl and the like.
[0021] [0021] The term "heteroaryl" when used alone or as part of a substituent group refers to a mono- or bicyclic-aromatic hydrocarbon ring structure including carbon atoms, as well as up to four heteroatoms selected from nitrogen, oxygen and sulfur. Heteroaryl rings can include a total of 5, 6, 9 or 10 atoms in the ring. The heteroaryl portion may be unsubstituted or one or more carbon atoms in the ring may be replaced by a halogen atom; an amino group; an amine group, including an amine group substituted with a —C1-Cecycloalkyl group, a —O-C -Ci3alkyl group or a —C1-Calkyl group; or a -C1-Cyizalkyl group. Halogen atoms include chlorine, fluorine, bromine and iodine. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thiophenyl (thienyl), oxazolyl, imidazolyl, purazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidine , indolyl, indol-6-yl, isoindolinyl, indazolyl, indazol-6-yl, —benzofuranyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, purinyl, quinolizinyl, quinolinyl, aminoquinolinyl, aminohaloquinolinyl, quinolin-7-yl, 2-amino yl-2-amino-3-yl-2 7-yl, 2-amino-3-chloroquinolin-7-yl, a 2-amino-3-fluoroquinolin-7-yl, 2 - ((cyclopropylmethyl) amino) quinolin- 7-yl, 2- (methylamino) quinolin-7-yl, 2- (methoxyamino) quinolin-7-yl, 2-aminoquinolin-7-yl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, imidazo [1,2-a] pyridinyl, substituted imidazo [1,2-a] pyridinyl, 3-methylimidazo [1,2-a] pyridin-7-yl, and the like.
[0022] [0022] When a range of carbon atoms is used in this document, for example, C1-Cç, all ranges, as well as the individual numbers of carbon atoms are encompassed. For example, “C1-C3” includes C1C3, C1-C2, C2.C3, C1, C2, € C3.
[0023] [0023] The term "C1-Céalg", when used alone or as part of a substituent group, refers to an aliphatic linker having 1, 2, 3, 4, 5, or 6 carbon atoms and includes, for example, - CH2-, -CH (CH3) -, -CH (CH3) -CH7-, and - CICH3), -. The term “-Coalgq-” refers to a bond. In some aspects, C1- Cçealg can be substituted with one or more -OH, -NH> 2, or halo substituents (for example, -F, -Cl, -Br, with -F being preferred).
[0024] [0024] "Pharmaceutically acceptable" means approved or approved by a regulatory agency of the federal or state government or the corresponding agency in countries other than the United States, or listed in the U.S. Pharmacopoeia or other pharmacopoeia generally recognized for use in animals, for example, in humans.
[0025] [0025] "Pharmaceutically acceptable salt" refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that has the desired pharmacological activity of the parent compound.
[0026] [0026] A "pharmaceutically acceptable excipient" refers to a substance that is non-toxic, biologically tolerable and biologically suitable for administration to a subject, as an inert substance, added to a pharmacological composition or used as a vehicle, carrier or diluent to facilitate the administration of an agent and that is compatible with it. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
[0027] [0027] A "solvate" refers to a physical association of a compound of Formula | with one or more solvent molecules.
[0028] [0028] The "subject" includes human beings. The terms "human", "patient" and "subject" are used interchangeably throughout this document.
[0029] [0029] "Treating" or "treating" any disease or disorder refers, in one embodiment, to improving the disease or disorder (ie, stopping or reducing the development of the disease or at least one of its clinical symptoms). In another modality, "treat" or "treatment" refers to the improvement of at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to the modulation of the disease or disorder, either physically (for example, stabilization of a discernible symptom), physiologically (for example, stabilization of a physical parameter), or both. In yet another modality, "treat" or "treatment" refers to the delay in the onset of the disease or disorder.
[0030] [0030] "Compounds of the present disclosure", and equivalent expressions, are intended to cover compounds of Formula |, as described in this document, as well as their subgenera, the expression of which includes stereoisomers (for example, entaniomers, diastereomers) and constitutional isomers (for example, tautomers) of compounds of Formula |,
[0031] [0031] As used in this document, the term "isotopic variant" refers to a compound that contains isotope ratios in one or more atoms that make up that compound that is greater than natural abundance. For example, an "isotopic variant" of a compound can be radiolabeled, that is, contain one or more radioactive isotopes or can be labeled with non-radioactive isotopes, such as deuterium ( H or D), carbon-13 (PC ), nitrogen-15 (* N) or similar. It should be understood that, in a compound in which this isotopic substitution is made, the following atoms, when present, can vary, so that, for example, any hydrogen can be H / D, any carbon can be "C or any nitrogen can be "* N, and that the presence and placement of such atoms can be determined according to the technique.
[0032] [0032] It should also be understood that compounds that have the same molecular formula, but differ in the nature or binding sequence of their atoms or in the arrangement of their atoms in space, are called "isomers". Isomers that differ in the arrangement of their atoms in space are called "stereoisomers", for example, diastereomers, enantiomers and atropisomers. The compounds of this disclosure can have one or more asymmetric centers; such compounds can therefore be produced as individual stereoisomers (R) or (S) in each asymmetric center or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include all stereoisomers and mixtures, racemic or otherwise, thereof. Where a chiral center exists in a structure, but no specific stereochemistry is shown for that center, both enantiomers, individually or as a mixture of enantiomers,
[0033] [0033] Disclosure is directed to compounds of Formula |: R a% & we Rº PAÁá AL - N o z Ri
[0034] [0034] According to the disclosure, R * at Fórumla | is -Co-Cçalg-C1- Cçealquila, -Co-Cealg-Cr-Cehaloalkyl, -Cr-Cealg-O-C1-Cçéalkyl, -Ca-Cealg-S-C1- Cçealquila, -Cr-Cealg-S-C1- Cealg-CO2H, -Ci-Ceéalg-arila, -Ci-Céóalg-O-arila, -C1- Cçealg-NH-arila, -C1-Cealg-S-arila, -Co-Cealg-heteroaryl, -C1-Cçalg- O-heteroaryl, - Cr1-Cealg-S-heteroaryl or -C1-Cçalg-NH-heteroaryl. In some respects, R * is -Co- Cçealg-C1-Cçealquila, -Co-Cealg-C1-Céhaloalkila, -Ci-Céalg-O-Ci-Cealquila, -Cr- Cçealg-S-C1-Cealquila, -Cr- Cçealg-S-C1-Cealg-CO2H, -Cr-Cealg-arila, -Ci-Céalg-O- aryl, -Cr-Cçalg-NH-arila, -Cr-Cçalg-S-arila, -Co-Cçalg-heteroarila , -Cr-Cçalg-O- heteroaryl, -C7-Cçalg-S-heteroaryl, -C7-Cçalg-NH-heteroaryl or -C (O) NH-aryl;
[0035] [0035] In some respects, R * is -Co-Cçalg-C1-Cçalquila, for example, -Coalg-Cialquila, -Cialg-Cialguila, -Coalg-Ciaalguila, -C3aalg-Cialgquila, -Caalg- Caialquila, -Csalg- Cialkyl, -Cealg-Caalquila, -Coalg-Coalquila, -Caalg-Caalquila, -
[0036] [0036] In other respects, R * is -Co-Cealg-C1-Cehaloalkyl, for example, -Coalg-Cihaloalkyl, -Cialg-Cahaloalquila, -Cralg-Cahaloalquila, -C3alg- Cihaloalquila, -Caalg-Cihaloalquila, -Csal Cahaloalkyl, -Céalg-Cihaloalquila, - Coalg-C> haloalkyl, -Caalg-C> haloalkyl, -Czalg-C> haloalkyl, -C3alg- Coahaloalquila, -Caalg-Cahaloalkyl, -Csalg-Chalo, - Coalg-C3haloalkyl, -Caalg-C3haloalkyl, -Czalg-C3haloalkyl, -C3alg- C3haloalkyl, -Caalg-C3haloalquila, -Csalg-C3haloalkyl, -Chalgal -Calhal -Alpha, -Czalg- Cahaloalkyl, -Caalg-Cahaloalkyl, -Csalg-Cahaloalkyl, -Ceçalg-Cahaloalkyl, - Coalg-Cshaloalkyl, -Cialg-Cshaloalkyl, -Czalg-Cshaloalkyl, -Calkal, -Calal, -Ceçalg-Cshaloalquila, - Coalg-Cehaloalquila, -Cialg-Cehaloalquila, -Czalg-Céhaloalquila, -C3alg- Cehaloalquila, -Caalg-Céhaloalkyl, -Csalg-Céhaloalquila, -Cé haloalkyl, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl fluoropentyl, chloromethyl, chloroethyl, chloropropyl, chlorobutyl, chloropentyl, bromomethyl, bromoethyl,
[0037] [0037] In some respects, R * is -Ci-Cealg-O-Ci-Cçéalquila, for example, -Cialg-O-Cialquila, -Caalg-O-Cyalkyl, -C3zalg-O-Cyalkyl, -Caalg-O- Caialquila, -Csalg-OC ,; alkyl, -Ceéalg-O-Cyalkyl, -Cialg-O-Coalkyl, -Czalg-O- Coalkyl, -C3alg-O-Coalkyl, -Caalg-O-Coalkyl, -Csalg-OC> alkyl, -Céalg-O-Caalkyl , -Cialg-O-Cizalquila, -Cazalg-O-Cizalquila, -C3zalg-O-Cizalquila, -Caalg-O- Czalquila, -Csalg-O-Cizalquila, -Cçalg-O-Cizalquila, -Cialg-O-Caalquila, -Caalg-O- Caalquila, -C3alg-O-Caalquila, -Caalg-O-Caalquila, -Csalg-O-Caalquila, -Ceçalg-O- Caalquila, -Cialg-O-Csalquila, -Czalg-O-Csalquila, - C3alg-O-Csalquila, -Caalg-O- Csalquila, -Csalg-O-Csalquila, -Cealg-O-Csalquila, -Cialg-O-Cçéalquila, -Cralg-O- Cçealquila, -Czalg-O-Cçalquila, -Ca -O-Cçealquila, -Csalg-O-Cçalquila, or -Cçalg-O- Crealquila. In some embodiments, R * is -CH2-0-CH3.
[0038] [0038] In some respects, R 'is -Ci-Cçealg-S-C1-Cálquila, for example, -Cialg-S-Cialquila, -Caalg-S-Cialgquila, -Czalg-S-Cialquila, -Caalg-S- Caialquila, -Csalg-S-Cialquila, -Cçalg-S-Cialquila, -Cialg-S-Coalquila, -Caalg-S- Coalquila, -C3zalg-S-Coalquila, -Caalg-S-Coalquila, -Csalg-S-Coalquila , -Cçalg-S- Coalquila, -Cialg-S-Czalquila, -Coralg-S-C3alkyl, -C3zalg-S-C3alkyl, -Caalg-S- Czalquila, -Csalg-S-Czalquila, -Céalgila-S-Czalquila, -Cialg-S-Caalquila, -Cralg-S- Caalquila, -C3zalg-S-Caalquila, -Caalg-S-Caalquila, -Csalg-S-Caalquila, -Cçalg-S- Caalquila, -Cialg-S-Csalquila, - Coralg-S-Csalquila, -C3zalg-S-Csalquila, -Caalg-S- Csalquila, -Csalg-S-Csalquila, -Cçalg-S-Csalquila, -Cialg-S-Cçealquila, -Cralg-S-
[0039] [0039] In some respects, R 'is -Ci-Cçalg-S-Ci-Céalg-CO> 2sH, for example, -Cialg-S- C7-Céalg-CO2H, -Caalg-S- Cr-Céalg-CO2sH, -Czalg-S-C1-Cçéalq- CO2H, -Caalg-S-Ci-Cealg-CO2H, -Csalg-S-Ci-Cealg-CO2H, -Cçéalg-S-C1i-Cealg-CO2H, -Ci-Ceéalg-S - Cialg-CO2H, -Ci-Cealg-S- Cralg-CO2H, -Cr-Ceéalg-S-Czalg- CO2H, -Ca-Cealg-S-Caalg-CO2H, -Ci-Céalg-S- Csalg-CO2H, - Ci-Céalg-S- Ceéalg- CO> 2H, and the like. In some embodiments, R * is -CH27-S-CH2CH2CH (NH> 2) - CO> 2H.
[0040] [0040] In some ways, R 'is -C1-Cçalg-arila, for example, -Ci1alg- arila, -Caalg-arila, -Czalg-arila, -Caalg-arila, -Csalg-arila, -Cçalg-arila, -CHaaryl, -CH (OH) -aryl, -CH (F) -aryl, -CH (NH2) -aryl, -CH (Me) -aryl, -C (Me) (OH) -aryl, and the like.
[0041] [0041] In some embodiments where R * is -C 1 -Cçéalg-aryl, the aryl is a mono- or bicyclic-aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, where one or more of the carbon atoms in the ring are optionally substituted with a halogen atom, a -C1- C3zalguila group, an amine-substituted -Ci-C3alguila group, a -Cx C3haloalkyl group, an amine group (i.e., -NH2), or an amine group substituted amino group.
[0042] [0042] In other embodiments where R * is -Cr-Cçalg-aryl, the aryl is a mono- or bicyclic-aromatic hydrocarbon ring structure with 6 or carbon atoms in the ring, where one or more carbon atoms in the ring is optionally substituted with a halogen atom, a -C1-Czalkyl group, an amine-substituted -C17-C3z alkyl group, an alkylamino-substituted -C1-C3 alkyl group, a hydroxy-substituted -C1-C3 alkyl group , a -C1-C3haloalkyl group, a -O-C1-C3haloalkyl group, an amine group (i.e., - NH2), or a substituted amine group.
[0043] [0043] In some embodiments where R * is -C1 -Cealg-aryl, the aryl is -4-chlorophenyl, 4-chloro-2- (hydroxymethyl) phenyl, 4-chloro-2- (aminomethyl) phenyl, 4- chloro-2 - ((methylamino) methyl) phenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, -3-fluoro-4-chlorophenyl, 3-methyl-4-chlorophenyl, 3-fluoro-4-trifluoromethylphenyl , 4-trifluoromethylphenyl, 4- (trifluoromethoxy) phenyl, 4-fluoro-3-trifluoromethylphenyl, benzo [d] [1,3] dioxazole, 4-isopropylphenyl or -3-chloro-4-fluorophenyl.
[0044] [0044] In some embodiments where R * is -C, -Cçéalg-aryl, the aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, -3-fluoro-4-chlorophenyl, 3-methyl-4-chlorophenyl, 3-fluoro-4-trifluoromethylphenyl, benzo [d] [1,3] dioxazole, or -3-chloro-4-fluorophenyl. Thus, in some embodiments, R * is -CHz-difluorophenyl, -CH2-3,4- difluorophenyl - -CH2-4-chlorophenyl, - -CH2-3-chloro-4-fluorophenyl, - -CH2-4-chloro- 3-fluorophenyl, -CH7-dichlorophenyl, -CH2-3,4-dichlorophenyl, -CH2-3-methyl-4-chlorophenyl, - CH2-3-fluoro-4-trifluoromethylphenyl, benzo [d] [1,3] dioxazole -5-ylmethyl, -CH (OH) -4-chlorophenyl, -CH (OH) -3,4-dichlorophenyl, -CH (OH) -3,4-difluorophenyl, -CH (OH) -3-fluoro-4 -chlorophenyl, -CH (OH) -3-chloro-4-fluorophenyl, -CH (OH) -3-methyl-4-chlorophenyl, -
[0045] [0045] In other modalities where R * is -C1-Cçalg-aryl, the aryl is - 4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, -3-fluoro-4-chlorophenyl, 3 -methyl-4-chlorophenyl, 3-fluoro-4-trifluoromethylphenyl, or -3-chloro-4-fluorophenyl. Thus, in some embodiments, R * is -CH> -difluorophenyl, -CH2-3,4-difluorophenyl.a -CH7-4- chlorophenyl, - -CH2-3-chloro-4-fluorophenyl, —-CH, 2- 4-chloro-3-fluorophenyl, —-CH7- dichlorophenyl, -CH, 2-3,4-dichlorophenyl, -CH7-3-methyl-4-chlorophenyl, -CH2-3-fluoro-4-trifluoromethylphenyl, -CH ( OH) -4-chlorophenyl, -CH (OH) -3,4-dichlorophenyl, -CH (0H) -3,4-difluorophenyl, -CH (OH) -3-fluoro-4-chlorophenyl, -CH (OH) -3-chloro-4-fluorophenyl, -CH (OH) -3-methyl-4-chlorophenyl, -CH - (OH) -3-fluoro-4-trifluoromethylphenyl, - -CH (F) -4- chlorophenyl, - CH (F) -3,4-dichlorophenyl, -CH (F) -3,4-difluorophenyl, -CH (F) -3-fluoro-4-chlorophenyl, -CH (F) -3-chloro-4-fluorophenyl , -CH (F) -3-methyl-4-chlorophenyl, -CH (F) -3- fluoro-4-trifluoromethylphenyl, -CH (NH2) -4-chlorophenyl, -CH (NH2.3,4-dichlorophenyl, - CH (NH, 2) -3,4-difluorophenyl, --CH (NH2) -3-fluoro-4-chlorophenyl, -CH (NH2) -3-chloro-4-
[0046] [0046] In some ways, R * is -Ci-Cçéalg-O-arila, for example, - Caialg-O-arila, -Cralg-O-arila, -C3zalg-O-arila, -Caalg-O-arila, -Csalg-O-aryl, -Cealq- O-aryl, -CH2-O-aryl, and the like. In some modalities in which R is -C 1 -Cçalg-O-aryl, -aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, -3-fluoro-4-chlorophenyl, 3-methyl-4-chlorophenyl , 3-fluoro-4-trifluoromethylphenyl, -3-chloro-4-fluorophenyl, -phenyl, -3- (aminomethyl) phenyl, 3- (urea) phenyl, 3-methyl-4-chlorophenyl, 3-fluoro-4- chlorophenyl, -3-fluoro-4-trifluoromethylphenyl, difluorophenyl, chlorophenyl, 4-chlorophenyl, - dichlorophenyl, - 3,4-dichlorophenyl, - bromophenyl, —iodophenyl or chlorofluorophenyl. Thus, in some embodiments, R * is -CH7-O-phenyl, -CH2-O- difluorophenyl, -CH2-0-3,4-difluorophenyl, -CH2-O0-4-chlorophenyl, -CH2-0-3- chloro-4-fluorophenyl, - -CH2-0-4-chloro-3-fluorophenyl, - -CH7-O-dichlorophenyl, - -CH2-0-3,4- dichlorophenyl, -CH2-0-3-methyl-4 -chlorophenyl, -CH7-0-3-fluoro-4-trifluoromethylphenyl, -CH7-0-3- (aminomethyl) phenyl, or -CH, -O0-3- (urea) phenyl. In some embodiments where R * is -C, -Cçalg-O-aryl, the aryl is 4-chloro-2- (hydroxymethyl) phenyl, -4-chloro-2- (aminomethyl) phenyl, -4-chloro-2 - ((methylamino) methyl) phenyl, 4-trifluoromethylphenyl, 4- (trifluoromide xi) phenyl, 4-fluoro-3-trifluoromethylphenyl or 4-isopropylphenyl.
[0047] [0047] In some respects, R * is -C1-Cçalg-NH-arila, for example, - Caialg-NH-arila, -Cralg-NH-arila, -C3zalg-NH-arila, -Caalg-NH-arila, -Csalg-NH-arila, -Cçealg-NH-arila, -CH2-NH-arila, and the like. In some modalities in which R ' is -Cr-C; alg-NH-aryl, -aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-
[0048] [0048] In some ways, R * is -C1-Cçéalg-S-arila, for example - Caialg-S-arila, -Caalg-S-arila, -C3zalg-S-arila, -Caalg-S-arila, -Csalg-S-aryl, -Cçalg-S- aryl, -CH2-S-aryl, and the like. In some embodiments where R * is -C1- Cçealg-S-aryl, -aryl is -4-chlorophenyl, - -3,4-dichlorophenyl, -3,4-difluorophenyl, -3-fluoro-4-chlorophenyl, 3-methyl-4-chlorophenyl, 3-fluoro-4-trifluoromethylphenyl, -3-chloro-4-fluorophenyl, -phenyl, -3- (aminomethyl) phenyl, 3- (urea) phenyl, 3-methyl-4-chlorophenyl , 3-fluoro-4-chlorophenyl, -3-fluoro-4-trifluoromethylphenyl, difluorophenyl, chlorophenyl, 4-chlorophenyl, - dichlorophenyl, - 3,4-dichlorophenyl, - bromophenyl, —iodophenyl or chlorofluorophenyl. Thus, in some embodiments, R * is -CH2-S-difluorophenyl, - CH7-S-3,4-difluorophenyl, -CH72-S-4-chlorophenyl, -CH72-S-3-chloro-4-fluorophenyl, - CH, 7- S-4-chloro-3-fluorophenyl, -CH2-NH-dichlorophenyl, -CH2-S-3,4-dichlorophenyl, -CH7-S-3-methyl-4-chlorophenyl, -CH2-NH- 3-fluoro-4-trifluoromethylphenyl, -CH2-NH-3- (aminomethyl) phenyl, -CH2-NH-3- (urea) phenyl. In some embodiments where R * is -C1-Cçalg- S-aryl, the aryl is 4-chloro-2- (hydroxymethyl) phenyl, -4-chloro-2- (aminomethyl) phenyl, -4-
[0049] [0049] In some respects, R 'is -Co-Cçalg-heteroaryl, for example, —Choalg-heteroaryl, —Cialg-heteroaryl, —Caalg-heteroaryl, —Ci3alg-heteraryl, - Caalg-heteroaryl, —-C salg- heteroaryl, and -Cçalg-heteroaryl. In other embodiments where R * is -Co-Cçalg-heteroaryl, heteroaryl is an indolyl, indol-6-yl, indazolyl, indazol-6-yl, quinolinyl, aminoquinolinyl, aminohaloquinolinyl, 2-amino-3-bromoquinolinyl group 7-yl, 2-amino-3-chloroquinolin-7-yl, 2-amino-3-fluoroquinolin-7-yl, 2 - ((cyclopropylmethyl) amino) quinolin-7-yl, 2- (methylamino) quinolin-7 -ila, or 2-aminoquinolin-7-yl. Thus, in some embodiments, R * is 2- (2-amino-3-bromoquinolin-7-yl) ethyl (i.e., -CH2CH7- (2-amino-3-bromoquinolin-7-yl)), 2- ( 2-amino-3-chloroquinolin-7-yl) ethyl, 2- (2-amino-3-fluoroquinolin-7-yl) ethyl, 2- (2 - ((cyclopropylmethyl) amino) quinolin-7-yl) ethyl, 2- (2- (methylamino) quinolin-7-yl) ethyl, 2- (2-aminoquinolin-7-yl) ethyl, (indol-6-yl) ethyl or (indazol-6-yl) ethyl. In some embodiments where R * is -C 9 -C 6 alg-heteroaryl, the heteroaryl is 3-methylimidazo [1,2-a] pyridin-7-yl, and R * is (3-methylimidazo [1,2- a] pyridin-7-yl) ethyl.
[0050] [0050] In some respects, R 'is —Ci-Cçalg-O-heteroaryl, for example, -C1alg-O-heteroaryl, —-C2alg-O-heteroaryl, —-C 3alg-O-heteroaryl, —-Caalg- O-heteraryl, -Csalg-O-heteroaryl, -Csalg-O-heteroaryl, and -Cçalg-O-heteroaryl. In some embodiments where R * is -C, -C 5 alg-O-heteroaryl, heteroaryl is an indolyl, indol-6-yl, indazolyl, indazol-6-yl, quinolinyl, quinolin-7-yl, aminoquinolinyl group , aminohaloquinolinyl, 2-amino-3-bromoquinolin-7-yl, 2-amino-3-chloroquinolin-7-yl, - 2-amino-3-fluoroquinolin-7-yl, - 2 - ((cyclopropylmethyl) amino) quinolin -7-yl, 2- (methylamino) quinolin-7-yl, 2- (methoxyamino) quinolin-7-yl, 3-methylimidazo [1,2-a] pyridin-7-yl or 2-aminoquinolin-7-yl . Thus, in some embodiments, R * is ((2-amino-3-bromoquinolin-7-yl) oxy) methyl (i.e., -CH2-0- (2-amino-3-bromoquinolin-7-yl)), ((2-amino-3-chloroquinolin-7-yl) oxy) methyl, ((2-amino-
[0051] [0051] In some modalities where R * is -C 7 -C 6; alg-O- heteroaryl, heteroaryl is an indolyl, indol-6-yl, indazolyl, indazol-6-yl, quinolinyl, group = quinolin-7-yl, aminoquinolinyl, - aminohaloquinolinyl, 2-amino-3-bromoquinolin-7 -yl, 2-amino-3-chloroquinolin-7-yl, 2-amino-3-fluoroquinolin-7-yl, 2- ((cyclopropylmethyl) amino) quinolin-7-yl, 2- (methylamino) quinolin-7- ila, 2- (methoxyamino) quinolin-7-yl, or 2-aminoquinolin-7-yl. Thus, in some embodiments, R * is ((2-amino-3-bromoquinolin-7-yl) oxy) methyl (i.e., -CH, -0- (2-amino-3-bromoquinolin-7-yl)) , (((2-amino-3-chloroquinolin-7-yl) oxy) methyl, ((2-amino-3-fluoroquinolin-7-yl) oxy) methyl, ((2 - ((cyclopropylmethyl) amino) quinolin-7 - yl) oxy) methyl, ((2- (methylamino) quinolin-7-yl) oxy) methyl, ((2-aminoquinolin-7-yl) oxy) methyl, ((lindol-6-yl) oxy) methyl) , 2- (methoxyamino) quinolin-7-yl) oxy) methyl, ((quinolin-7-yl) oxy) methyl or ((indazol-6-yl) oxy) methyl.
[0052] [0052] In other embodiments where R * is -C1-Cçealg-O-heteroaryl, heteroaryl is an indolyl, indol-6-yl, indazolyl, indazol-6-yl, quinolinyl, aminoolinolinyl, aminohaloquinolinyl, 2-amino group -3-bromoquinolin-7-yl, 2-amino-3-chloroquinolin-7-yl, - 2-amino-3-fluoroquinolin-7-yl, - 2 - ((cyclopropylmethyl) amino) quinolin-7-yl, 2 - (methylamino) quinolin-7-yl, or 2-aminoquinolin-7-yl. Thus, in some embodiments, R * is ((2-amino-3-bromoquinolin-7-yl) oxy) methyl (i.e., - CH2-0- (2-amino-3-bromoquinolin-7-yl)), ((2-amino-3-chloroquinolin-7-yl) oxy) methyl, ((2-amino-3-fluoroquinolin-7-yl) oxy) methyl, ((2 - ((cyclopropylmethyl) amino) quinolin-7- il) oxy) methyl, ((2- (methylamino) quinolin-7-yl) oxy) methyl, ((2-aminoquinolin-7-yl) oxy) methyl, ((((indol-6-yl) oxy) methyl) , or ((indazol-6-yl) oxy) methyl.
[0053] [0053] In some respects, R'is —CiCçalg-S-heteroaryl, for example, -Cialg-S-heteroaryl, -C2alg-S -heteroaryl, -C3alg-S -heteroaryl, -Caalg- S-heteraryl, - C salg-S -heteroaryl, —Cc salg-S -heteroaryl, and -Cçalg-S-heteroaryl. In other embodiments where R * is -C, -Cçéalg-S-heteroaryl, heteroaryl is an indolyl, indol-6-yl, indazolyl, indazol-6-yl, - quinolinyl, - aminoquinolinyl, aminohaloquinolinyl, 2-amino group -3-bromoquinolin-7-yl, 2-amino-3-chloroquinolin-7-yl, 2-amino-3-fluoroquinolin-7-yl, - 2 - ((cyclopropylmethyl) amino) quinolin-7-yl, 2- (methylamino) quinolin-7-yl, or 2-aminoquinolin-7-yl. Thus, in some embodiments, R * is ((2-amino-3-bromoquinolin-7-yl) oxy) methyl (i.e., -CH2-S- (2-amino-3-bromoquinolin-7-yl)), ((2-amino-3-chloroquinolin-7-yl) thio) methyl, ((2-amino-3-fluoroquinolin-7-yl) thio) methyl, ((2 - ((cyclopropylmethyl) amino) quinolin-7- il) thio) methyl, ((2- (methylamino) quinolin-7-yl) thio) methyl, ((2-aminoquinolin-7-yl) thio) methyl, (((lindol-6-yl) thio) methyl) , or ((indazol-6-yl) thio) methyl. In some modalities in which R is -C1-Cçéalg-S-heteroaryl, heteroaryl is 3-methylimidazo [1,2-a] pyridin-7-yl, and R 'is (((3-methylimidazo [1,2-a] pyridin-7-yl ) uncle) methyl.
[0054] [0054] In some respects, R'is —Ci-Cçsalg-NH-heteroaryl, for example, -Cialg-NH-heteroaryl, -Caralg-NH-heteroaryl, -C3zalg-NH-heteroaryl, - Caalg-NH-heteraryl, -Csalg-NH-heteroaryl, -Csalg-NH-heteroaryl, and -Cçalg-NH-heteroaryl. In other embodiments where R * is -Ci-Céalg-NH-heteroaryl, heteroaryl is an indolyl, indol-6-yl, indazolyl, indazol-6-yl, quinolinyl, aminoquinolinyl, aminohaloquinolinyl, 2-amino-3- bromoquinolin-7-yl, 2-amino-3-chloroquinolin-7-yl, - 2-amino-3-fluoroquinolin-7-yl, - 2 - ((cyclopropylmethyl) amino) quinolin-7-yl, 2- (methylamino ) quinolin-7-yl, or 2-aminoquinolin-7-yl. Thus, in some embodiments, R * is ((2-amino-3-bromoquinolin-7-yl) oxy) methyl (i.e., - CH2-NH- (2-amino-3-bromoquinolin-7-yl)), ((2-amino-3-chloroquinolin-7-yl) amino) methyl, ((2-amino-3-fluoroquinolin-7-yl) amino) methyl, ((2 - ((cyclopropylmethyl) amino) quinolin-7- il) amino) methyl, ((2- (methylamino) quinolin-7-yl) amino) methyl, ((2-
[0055] [0055] In some ways, R 'is —C (O) -NH-aryl. In some embodiments where R * is -C (O) -NH-aryl, -aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, -3-fluoro-4-chlorophenyl, 3-methyl-4-chlorophenyl, 3-fluoro-4-trifluoromethylphenyl, -3-chloro-4-fluorophenyl, -phenyl, -3- (aminomethyl) phenyl, 3- (urea) phenyl, 3-methyl-4-chlorophenyl , 3-fluoro-4-chlorophenyl, -3-fluoro-4-trifluoromethylphenyl, difluorophenyl, chlorophenyl, 4-chlorophenyl, dichlorophenyl, 3,4-dichlorophenyl, bromophenyl, iodophenyl, chlorofluorophenyl or benzo [d] [1,3] dioxazol . In some embodiments where R * is -C (O) -NH-aryl, the aryl is -4-chloro-2- (hydroxymethyl) phenyl, -4-chloro-2- (aminomethyl) phenyl, -4-chloro- 2 - ((methylamino) methyl) phenyl, 4-trifluoromethylphenyl, 4-fluoro4-trifluoromethylphenyl, 4-isopropylphenyl or -4- (trifluoromethoxy) phenyl.
[0056] [0056] In some ways, R * is C1-Cealg-S (O) aryl, for example, - Cialg-S (O) aryl, -Coalg-S (O) aryl, -C3alg-S (O) aryl, -Caalg-S (O) aryl, -Csalg- S (O) aryl, and -Cçalg-S (O) aryl, where aryl is phenyl, naphthyl, fluorophenyl, difluorophenyl, fluoronaftila, chlorophenyl, bromophenyl, iodophenyl, methylphenyl and similar.
[0057] [0057] In some respects, R * is C1-Cçalg-S (O) zarila, for example - Cialg-S (O) zarila, -Cralg-S (O)> arila, -C3zalg-S (O) zarila , -Caalg-S (O) saril, -Csalg- S (O) zaryl, and -Cçealg-S (O) zaryl, where aryl is phenyl, naphthyl, fluorophenyl, difluorophenyl, fluoronaftila, chlorophenyl, bromophenyl, iodophenyl, methylphenyl and the like.
[0058] [0058] In some respects, R * is —Ci-Cçealg-S (O) heteroaryl, for example, -Cialg-S (O) heteroaryl, -C2alg-S (O) heteroaryl, -Czalg-S (O) heteroaryl , -
[0059] [0059] In some respects, Rº is —Ci-Cçéalg-S (O)> »heteroaryl, for example, -Caalg-S (O)> heteroaryl, -C2alg-S (O) aheteroarila, -C3alg-S (O )> heteroaryl, -Caalg-S (O) oheteroaryl, -Csalg-S (O) aheteroaryl, and -Csalg-S (O) »heteroaryl, where heteroaryl is indolyl, y indol-6-yl, indazolyl, indazol- 6-yl, quinolinyl, aminoquinolinyl, aminohaloquinolinyl, 2-amino-3-bromoquinolin-7-yl, 2-amino-3-chloroquinolin-7-yl, 2-amino-3-fluoroquinolin-7-yl, 2 - (( cyclopropylmethyl) amino) quinolin-7-yl, 2- (methylamino) quinolin-7-yl or 2-aminoquinolin-7-yl.
[0060] [0060] In the compounds of the present disclosure, R is -Cr-Cealkyl, - Cir-Cehaloalkyl, -C2-Cealkenyl, or -C2-Cç.
[0061] [0061] In some modalities, R is -C1-Cç alkyl, -C2-Cçalquenila, or -C2-Cçealquinila.
[0062] [0062] In some respects, Rº is -C1-Cç alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. In some modalities, R it's methyl.
[0063] [0063] In other respects, R º is -C1-C; ç haloalkyl, for example, - CF3 or -CHF2. In some modalities, R is -CF3
[0064] [0064] In some respects, RºC2-Kalkenyl, preferably -C> 2- Caalkenyl, for example, vinyl, allyl, and the like.
[0065] [0065] In some aspects, RºC, -Cçalquinila, preferably -C2- Caalquinila, for example, ethinyl, propargila and the like.
[0066] [0066] In the compounds of the present disclosure, R is H, halo, -C1- Crealquila, or NHs. So, in some modalities, R is H. According to other modalities, R º is halo, for example F, Cl, Br, or |. In other modalities, R is -Ci-Cealkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl and the like. So, in some modalities, R represents a methyl group (Me). In still other modalities, R is NH>. In the preferred modalities, Rº is H.
[0067] [0067] In the compounds of the present disclosure, Rº is H, halo, -Cx- Cálquila, -C1-Céalg-O - C1-Cçéalquila, -NRÍRS, -NHCONRÓRS, NHC (S) NRÓRE, -NH- O-Ró , or -NH-NRºRÔ. In some modalities, Rº is halo, -Ci-Cealquila, -C1- Cçealg-O - C1-Cçalquila, -NRÍRó, -NHCONRRS, NHC (SINRÓRO, -NH-O-R $, or -NH- NRºRÔ,
[0068] [0068] In some respects, Rº is H.
[0069] [0069] In some respects, Rº is halo, for example chlorine, fluorine, bromine, or iodine. In some modalities, Rº is chlorine.
[0070] [0070] In some respects, Rº is -C1-Cçalquila, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. In some modalities, Rº is methyl.
[0071] [0071] In some respects, Rº is -Ci-Cçealg-O-Ci-Cçalquila, for example, -Ci-Cealg-O-Ci-Cealquila, -Ci-Csalg-O-Ci-Ceéalquila, -Ci-Caalg- O0-C1- Cçsalquila, - -Cr-C3zalg-O-Ci-Cçalquila, - -Cr-Caalg-O-Ci-Cçéalquila, - -Cialg-0-C1- Cçalquila, -Ci-Cçalg-O-Ci-Csalguila , -Ci-Cçalg-O-Ci-Caalquila, -Ci-Céóalg-O0-C1- Czalkquila, -Ca-Céalg-O-C1r-Caalquila, or -Ci-Ceéalg-O-Cialquila. In some modalities, Rº is -CH2CH2-0-CHs3.
[0072] [0072] In some respects, Rº is -NRºRº. Thus, in some modalities where Rº and Rº are both H, Rº is -NH>. In some modalities where Rº and Rº are both methyl, Rº is —-N (CH3)>. In modalities where Rº is H and Rº is methyl, Rº is -NH (CH3).
[0073] [0073] In some respects, Rº is -NHCONR $ RS ', Thus, in some modalities in which Rº and Rº are both H, Rº is -NHCONH> 2. In some modalities where Rº and Rº are both methyl, Rº is -NHCON (CH3). In modalities where Rº is H and Rº is methyl, Rº is -NHCONHCH ;.
[0074] [0074] In some respects, Rº is NHC (S) NRºRÔ. Thus, in some modalities where Rº and Rº are both H, Rº is -NHC (S) NH2. In some modalities in which Rº and Rº are both methyl, Rº is -NHC (S) N (CH3) 2. In modalities where Rº is H and Rº is methyl, Rº is -NHC (S) NHCH3.
[0075] [0075] In some respects, Rº is -NH-O-Rº. In some modalities where Rº is C1-Cealquila, for example, methyl, Rº is -NH-OCH3. In some modalities where R $ is ethyl, Rº is -NH-OCH, CH3. In some modalities where R * º is ethyl, Rº is -NH-OH.
[0076] [0076] In some respects, Rº is -NH-NRÓRÍ. In some modalities where Rº and Rº are both H, Rº is -NH-NH>. In modalities where Rº and Rº are both C 17 -C; alkyl, for example, methyl, Rº represents a —NH-N (CH3) 2 group. In modalities where Rº is HRº is C 1 -C is alkyl, for example, methyl, Rº is -NH-N (CH3)>.
[0077] [0077] It will be evident that when Rº is -NH-O-R $ or -NH-NRºRÔ, the compounds of Formula | they can exist as tautomers having geometry (E) - or (Z) - in the exocyclic carbon-nitrogen double bond. Formula compounds | described and claimed herein are intended to cover all such tautomers and geometric isomers. The representation of a particular tautomer or geometric isomer is not intended to be limiting. For example, when Rº is -NH-O-R $, compounds of Formula | can be represented by any of the following equivalent structures:
[0078] [0078] Similarly, when Rº is -NH-NR $ RÓ ', compounds of Formula | can be represented by any of the following equivalent structures:
[0079] [0079] In the compounds of the present disclosure, R * is H, halo, -Cr- Cálquila, -C1-Céhaloalkyl, -C7-Cçéalquenila, -C 7-Cgalquinila, or -Cr-Céçalg-OH. In some respects, Rº is H.
[0080] [0080] In other respects, R * is halo, for example, fluorine, chlorine, bromine, or iodine. In some embodiments, R * is fluorine.
[0081] [0081] In some respects, Rº is -C1-Cçalquila, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. In other respects, Rº -C7-Crçalquenila, preferably -C> - Caalquenila, for example, vinyl, alila, and the like. In still other aspects, R -
[0082] [0082] In other respects, Rº is -C1-C; ç haloalkyl, for example, - CF3 or -CHF, 2. In some embodiments, R * is -CF; 3
[0083] [0083] In some respects, Rº is -C1-Cçalg-OH, for example, -C1- Cçealg-OH, -C1-Csalg-OH, -C1i-Caalg-OH, -C1-C3alg-OH, -Cr- Caralg-OH, or —Cialg- OH. In some embodiments, R * is -CH2OH.
[0084] [0084] In the compounds of the present disclosure, Rº and Rº are each independently H, C1-C 6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and Similar) or -C1-Cçealg-O C1-Cçalquila (eg, Cr-Cçalg-OC -Cçalquila, Cr-Csalg-OC1-Cçalquila, Cr-Caalg-OC -Cçéalquila, C1- Cz3alg-OC -Cçalquila, C; - Caalg-OC, 7-Cçalquila, Cralg-OC, 1-Cçalquila, Cr-Cçalg-OC1- Csalquila, - Ci-Cealg-OC1-Caalgquila, - Ca-Cealg-OC1-Cizalguila, - Ci-Cealg-OC1- Coalquila , or C1-Céalg-O Caalquila).
[0085] [0085] In some modalities, Rº is H or Ci-Cçalguila. In some embodiments, R6 is H or C1-Cealkyl.
[0086] [0086] In some modalities, Rº and Rº are each H.
[0087] [0087] In other modalities, Rº and Rº are each, independently, C, 1-Cçéalquila. Thus, in some modalities, Rº is methyl and R $ is methyl.
[0088] [0088] In some respects, Rº is Ci-Cçalquila and Rº is H. Thus, in some modalities, R $ is methyl and Rº is H.
[0089] [0089] In other respects, Rº and Rº are each, independently, -C1-Cçéalg-OC1-Cçealquila.
[0090] [0090] In other respects, Rº is C1-Cealg-OC1-Cealquia and Rº is H.
[0091] [0091] In some disclosure modalities, Rº and Rº, together with the atom to which they are attached, form a C7z ring
[0092] [0092] Preferred modalities are those in which R * is -CH, 2-O-CH3, -CH2-S-CH3, —CH2-S-CHCH2CH (NH2) -CO2H, -CH (OH) -4-chlorophenyl , - CH (0H) -3,4-dichlorophenyl, -CH (0H) -3,4-difluorophenyl, -CH (OH) -3-fluoro-4-chlorophenyl, - -CH (OH) -3-chloro- 4-fluorophenyl, - -CH (OH) -3-methyl-4-chlorophenyl, —- CH (OH) -3-fluoro-4-trifluoromethylphenyl, -CH (F) -4-chlorophenyl, -CH (F) - 3,4- dichlorophenyl, -CH (F) -3,4-difluorophenyl, -CH (F) -3-fluoro-4-chlorophenyl, -CH (F) - 3-chloro-4-fluorophenyl, -CH (F ) -3-methyl-4-chlorophenyl, -CH (F) -3-fluoro-4-trifluoromethylphenyl, - -C (Me) (OH) -4-chlorophenyl, - -C (Me) (OOH) -3, 4-dichlorophenyl, - C (Me) (0H) -3,4-difluorophenyl, -C (Me) (OH) -3-fluoro-4-chlorophenyl, -C (Me) (OH) -3- chlorine-4 -fluorophenyl, -C (Me) (0H) -3-methyl-4-chlorophenyl, -C (Me) (OH) -3-fluoro-4-trifluoromethylphenyl, -CH2-O-phenyl, -CH2-O-difluorophenyl , -CH2-0-3,4-difluorophenyl, - CH7-0-4-chlorophenyl, -CH2-0-3-chloro-4-fluorophenyl, -CH2-0-4-chloro-3-fluorophenyl, - CH7- O-dichlorophenyl, -CH2-0-3,4-dichlorophenyl, -CH2-0-3-me tyl-4-chlorophenyl, -CH7- 0-3-fluoro-4-trifluoromethylphenyl, -CH2-0-3- (aminomethyl) phenyl, -CH7-0-3- (urea) phenyl, ((2-amino-3 -bromoquinolin-7-yl) oxy) Methyl (ie, -CH, -O- (2-amino-3-bromoquinolin-7-yl)), ((2-amino-3-chloroquinolin-7-yl) oxy) Methyl, ((2-amino-3-fluoroquinolin-7-yl) oxy) methyl, ((2- (methylamino) quinolin-7-yl) oxy) methyl, ((2-aminoquinolin-7-yl) oxy) mMethyl , ((indol-6-yl) oxy) methyl, ((indazol-6-yl) oxy) methyl, 2- (2-aminoquinolin-7-yl) ethyl, ((2-aminoquinolin-7-iDtio) methyl, - (((2-aminoquinolin-7-i) jamino) methyl. Other preferred modalities are those in which R'é ((3-
[0093] [0093] The preferred modalities are those in which R it's methyl.
[0094] [0094] In some respects, the present disclosure is directed to compounds of Formula IA O »" and S Re DO ds = o R -A where R 'is -Co-Cçalg-C1-Cçealquila, -Co-Cealg-C1 -Cehaloalkyl, -C1- Cçealg-O-C1-Cçealquila, -C1-Cealg-S-C1-Cçealquila, -Cai-Cealg-S-C1a-Cealg-CO2H, -C1- Cçalg-arila, -C7-Cçalg- O-aryl, -Co-Cçealg-heteroaryl, -C, -Cçalg-O-heteroaryl, -C1- Cçealgq-S-heteroaryl, or -Ci-Céalg-NH-heteroaryl; Rº is methyl, trifluoromethyl, ethynyl, or vinyl ; Rº is halo, Ci-Cçalquila, -NHC (O) NRÓRO, —NRÓRÔ, -NH-O-Rº or - NH-NRÓRÔ: Rº is H orF; and Rº and Rº are each, independently, H or -C1 - Cçalquila.
[0095] [0095] In some embodiments, compounds of the general formula IA are those in which R * is -Co-Cçalg-C1-Cçalquila, -Co-Cçealg-C1-Céhaloalkyl, -C1- Cçealg-O-C1-Cçealquila, - C1-Cealg-S-C1-Cçealquila, -Cai-Cealg-S-C1a-Cealg-CO2H, -C1- Cçalg-arila, -C1-Cçalg-O-arila, -Co-Cealg-heteroaryl, -C1-Cçealg -O-heteroaryl, -C1- Cçalq-S-heteroaryl, or -C7-Cçalg-NH-heteroaryl; R it is methyl, ethinyl, or vinyl; Rº is halo, Cr-Céalkyl, -NHC (O) NRÓRS ', —NRÓRS', -NH-O-R $ or -NH-NRÓRS; R is H or F; and Rº and Rº are each, independently, H or -C1-Cçalquila.
[0096] [0096] In some embodiments, compounds of general formula I-A are those in which R * is -C1-Cçalg-aryl or -C1-Cçalg-O-heteroaryl; Rº is methyl, ethinyl, or vinyl; Rº is halo, Cr-Cçalquila, -NHC (O) NRRS, —NRÓRO ', -NH-O-R $ or - NH-NRÓRO'; R is H orF; and Rº and Rº are each, independently, H or -Cr- Cçalquila.
[0097] [0097] In some embodiments, compounds of general formula I-A are those in which R * is -C1-Cçalg-O-heteroaryl; R º is methyl, ethinyl, or vinyl; Rº is halo, C1-C6alkyl, -NHC (O) NRÓRS, —NRóRÔ, -NH-O-Rº or -NH-NRÓRÔ; R5 is H or F; and R6 and R6 'are each, independently, H or -C1-Cçéalkyl.
[0098] [0098] In some embodiments, compounds of the general formula I-A are those in which R * is -Cr-Cçalg-aryl; R it is methyl, ethinyl, or vinyl; Rº is halo, C1-C6alkyl, -NHC (O) NRÓRS ', —NRÓRS, -NH-O-Ró or -NH-NRÓR6; R5 is HouF; and R6 and R6 'are each, independently, H or -C1-Cecealkyl.
[0099] [0099] In some embodiments, compounds of general formula IA are those in which R * is -C1-Cç alg-aryl in which the aryl is a mono- or bicyclic-aromatic hydrocarbon ring structure having 6 or 10 atoms of carbon in the ring, where one or more of the carbon atoms where the ring is optionally substituted with a halogen atom, a -C1-Czalkyl group, an amine-substituted -C7-Czalkyl group, a -C17-C3haloalkyl group, an amine group (i.e., -NH2), or a substituted amino group; - R it is methyl, ethinyl or vinyl; Rº is halo, C1-Cealquila, -NHC (O) NRÓRS, —NRRÓ, -NH-O-Ró or -NH-NRÓRE "; RºéHouF; andRºeRº are each, independently, H or -C1-Cç alkyl.
[0100] [0100] In some respects, the present disclosure is directed to compounds of Formula | -B
[0101] [0101] In some preferred embodiments, compounds of Formula | -B are those in which R * is ((2-amino-3-bromoquinolin-7-yl) oxy) methyl (i.e., CH2-0- (2- amino-3-bromoquinolin -7-yl)), ((2-amino-3-chloroquinolin-7-yl) oxy) methyl, ((2-amino-3-fluoroquinolin-7-yl) oxy) methyl, (( (2- (methylamino)) quinolin-7-yl) Ooxy) methyl, ((2-aminoquinolin-7-yl) oxy) methyl, ((indol-6-yl) oxy) methyl, ((indazol-6-yl ) Oxy) methyl, 2- (2-aminoquinolin-7-yl) ethyl, ((2-aminoquinolin-7-yl) thio) methyl or ((2-aminoquinolin-7-yl) amino) methyl; Rº is -NH2, -NH-O-CH3 or -NH-NH-CH 3. and Rº is HourF.
[0102] [0102] In some preferred embodiments, compounds of Formula IB are those in which R * is ((quinolin-7-yl) oxy) methyl, ((2-amino-3-bromoquinolin-7-yl) oxy) methyl ( that is, -CH 2.0- (2-amino-3-bromoquinolin-7-yl)), ((2-amino-3-chloroquinolin-7-yl) oxy) methyl, ((((2-amino-3-fluoroquinolin -7-yl) oxy) methyl, ((2- (methylamino) quinolin-7-yl) oxy) methyl, ((2- (methoxyamino) quinolin-7-yl) Oxy) methyl, (((2-aminoquinolin- 7-yl) oxy)) methyl, ((indol-6-yl) oxy) methyl, ((indazol-6-yl) oxy) methyl, 2- (2-aminoquinolin-7-yl) ethyl, (((2 -aminoquinolin-7-yl)) thio) methyl, ((3-
[0103] [0103] In some preferred embodiments, compounds of Formula IB are those in which R * is ((quinolin-7-yl) oxy) methyl, ((2-amino-3-bromoquinolin-7-yl) oxy) methyl ( that is, -CH2-0- (2-amino-3-bromoquinolin-7-yl)), ((2-amino-3-chloroquinolin-7-yl) oxy) methyl, (((2-amino-3- fluoroquinolin-7-yl) oxy) methyl, ((2- (methylamino) quinolin-7-yl) oxy) methyl, ((2- (methoxyamino) quinolin-7-yl) oxy) methyl, (((2-aminoquinolin -7-yl) oxy)) methyl, (((indol-6-yl) oxy) methyl, (((indazol-6-yl) Ooxy) methyl, 2- (2-aminoquinolin-7-yl) ethyl, (((( 2-aminoquinolin-7-yl)) thio) methyl, ((3-methylimidazo [1,2-a] pyridine-7yl) oxy) methyl, or ((2-aminoquinolin-7-yl) amino) methyl; Rº is -NRÓR ', -NH-OR $ ó or -NH-NRºRó' Rº is H or F; and Rº and R6 are each, independently, H or -C1-Cçéalquila.
[0104] [0104] In some respects, the present disclosure relates to compounds of Formula | -B where R * is -C1-Cealg-aryl, Rº is -NRÓRS ', -NH-O-Rº or -NH-NRÓRS: Rº is HorF; eRºeR ”are each, independently, H or -C1- Cçalquila.
[0105] [0105] In some embodiments, compounds of Formula | -B are those in which R * is -C1 -Cç alg-aryl in which the aryl is a mono- or bicyclic-aromatic hydrocarbon ring structure having 6 or 10 atoms of carbon in the ring, where one or more of the carbon atoms in which the ring is optionally substituted with a halogen atom, a -C1-Czalkyl group, an amine-substituted -C1-Czalkyl group, a -C1-C3haloalkyl group , an amino group (i.e., -NH2), or a substituted amino group; Rº is -NRºRÔ ', -NH-O- Ró or -NH-NRÓRó; RºéHouF; eRºeR ”are each, independently, H or -C1-Cç6 alkyl.
[0106] [0106] In some preferred embodiments, compounds of Formula | -B are those in which R is -Cialg-aryl, R4 is —-NRÓRS, -NH-O-R $ or -
[0107] [0107] In other preferred embodiments, compounds of Formula | -B are those in which R * is -C, alg-aryl, Rº is -NH2, -NH-O-CH; 3 or -NH-NHCH3. and Rº is HourF.
[0108] [0108] In other preferred embodiments, compounds of Formula | -B are those in which R * is -CH (OH) -4-chlorophenyl, -CH (OH) -4-chloro-2- (hydroxymethyl) phenyl, - CH (OH) -3,4-dichlorophenyl, -CH (OH) -3,4-difluorophenyl, -CH (OH) -3-fluoro-4-chlorophenyl, -CH (OH) -3-methyl-4-chlorophenyl , -CH (OH) -3-fluoro-4-trifluoromethylphenyl, -CH (OH) -4-trifluoromethylphenyl, -CH (OH) - 4- (trifluoromethoxy) phenyl, -CH (0 H) -4-fluoro-3 -trifluoromethylphenyl, -CH (OH) -benzo [d] [1,3] dioxazolyl, -CH (OH) - 4-isopropylphenyl or -CH (OH) -3-chloro-4-fluorophenyl; Rº is —-NRÓRS ', -NH- O-Rº or -NH-NRºRó; RóéHouF; eRºeR ”are each, independently, H or -Ci-Cçalquila.
[0109] [0109] In other preferred embodiments, compounds of Formula | -B are those in which R * is -CH (OH) -4-chlorophenyl, -CH (OH) -4-chloro-2- (hydroxymethyl) phenyl, - CH (OH) -3,4-dichlorophenyl, -CH (OH) -3,4-difluorophenyl, -CH (OH) -3-fluoro-4-chlorophenyl, -CH (OH) -3-methyl-4-chlorophenyl , -CH (OH) -3-fluoro-4-trifluoromethylphenyl, -CH (OH) -4-trifluoromethylphenyl, -CH (OH) - 4- (trifluoromethoxy) phenyl, -CH (0 H) -4-fluoro-3 -trifluoromethylphenyl, -CH (OH) -benzo [d] [1,3] dioxazolyl, -CH (OH) - 4-isopropylphenyl or -CH (OH) -3-chloro-4-fluorophenyl; Rº is -NH2-NH-O-CH3 or -NH-NH-CH3. and Rº is H or F.
[0110] [0110] In other preferred embodiments, compounds of Formula | -B are those in which R * is -CH2-4-chloro-2- (hydroxymethyl) phenyl, -CH 2.4-chloro-2- (aminomethyl) phenyl, - CH 2 (4-chloro-2- (methylamino) methyl) phenyl, -CH 23,4-dichlorophenyl, -CH 2.benzo [d] [1,3] dioxazolyl; Rº is H, z-NRÓR6 ', -NH-O-Rº or -NH-
[0111] [0111] In other preferred embodiments, compounds of Formula | -B are those in which R * is -CH> 4-chloro-2- (hydroxymethyl) phenyl, -CH 24-chloro-2- (aminomethyl) phenyl, - CH 2 (4-chloro-2- (methylamino) methyl) phenyl, -CH 23,4-dichlorophenyl, -CH 2.benzo [d] [1,3] dioxazolyl; Rº is H, -NH 2, -NH-OH, -NH-O-CH3 or -NH-NH-CH3, and Rº is HourF.
[0112] [0112] In other preferred embodiments, compounds of Formula | -B are those in which R * is -CH (OH) -4-chlorophenyl, -CH (OH) -3,4- dichlorophenyl, -CH (OH) - 3,4-difluorophenyl, -CH (OH) -3-fluoro-4-chlorophenyl, -CH (OH) -3-chloro-4-fluorophenyl, -CH (OH) -3-methyl-4-chlorophenyl, -CH (OH) -3- fluoro-4-trifluoromethylphenyl, - -C (Me) (OH) -4-chlorophenyl, - -C (Me) (OOH) -3,4-dichlorophenyl, - C (Me) (0H) -3,4-difluorophenyl, - C (Me) (OOH) -3-fluoro-4-chlorophenyl, -C (Me) (OH) -3-chloro-4-fluorophenyl, -C (Me) (OH) - 3-methyl-4-chlorophenyl, or —C (Me) (OH) -3-fluoro-4-trifluoromethylphenyl; Rº is -NRÓRS, -NH-O-Rº or -NH-NRÓRS; Rº is HouF, and RºeRº are each, independently, H or -C1-Cçalquila.
[0113] [0113] In yet other preferred embodiments, compounds of Formula | -B are those in which R * is -CH (OH) -4-chlorophenyl, -CH (OH) -3,4- dichlorophenyl, -CH (OH) -3,4-difluorophenyl, -CH (OH) -3-fluoro-4-chlorophenyl, -CH (OH) -3-chloro-4-fluorophenyl, -CH (OH) -3-methyl-4-chlorophenyl, - CH (OH) -3-fluoro-4-trifluoromethylphenyl, - -C (Me) (OH) -4-chlorophenyl, - -C (Me) (OOH) -3,4-dichlorophenyl, - C (Me) (0H ) -3,4-difluorophenyl, -C (Me) (OH) -3-fluoro-4-chlorophenyl, -C (Me) (OH) -3-chloro-4-fluorophenyl, -C (Me) (OH) -3-methyl-4-chlorophenyl or —-C (Me) (OH) -3-fluoro-4-trifluoromethylphenyl; R ° is -NH2, -NH-O-CH3 or -NH-NHCH3; and Rº is HouF.
[0114] [0114] In yet other preferred embodiments, compounds of Formula | -B are those in which R * is -CH (OH) -4-chlorophenyl, -CH (OH) -3,4- dichlorophenyl, or -CH (OH ) -3-methyl-4-chlorophenyl; Rº is —-NH>, -NH-O-CH3 or -NH-
[0115] [0115] In some respects, the present disclosure relates to compounds of Formula | -B where R * is -C1-Cçéalg-aryl, Rº is -C1-C6 alkyl; and Rº is H or F. Some preferred modalities are those in which R * is -Cialg-aryl, eR is-CHzeR éHourF.
[0116] [0116] In some respects, the present disclosure relates to compounds of Formula | -B wherein R * is -C1i-Cealg-aryl wherein the aryl is a mono- or bicyclic-aromatic hydrocarbon ring structure having 6 or 10 ring carbon atoms, where one or more ring carbon atoms is optionally substituted with a halogen atom, a -C1-C3alkyl group, an amine-substituted -C1-C3alkyl group, a -C1-C3haloalkyl group, an amino group (i.e., -NH2), or a substituted amino group; Rº is -C1i-Cçalquila; and R éHourF.
[0117] [0117] In preferred embodiments, compounds of Formula | IB are those in which R * is -CH (OH) -4-chlorophenyl, -CH (OH) -4-chloro-2- (hydroxymethyl) phenyl, -CH ( OH) -3,4-dichlorophenyl, -CH (OH) -3,4-difluorophenyl, -CH (OH) -3-fluoro-4-chlorophenyl, -CH (OH) -3-methyl-4-chlorophenyl, - CH (OH) -3-fluoro-4-trifluoromethylphenyl, -CH (OH) -4-trifluoromethylphenyl, -CH (OH) - 4- (trifluoromethoxy) phenyl, -CH (0 H) -4-fluoro-3-trifluoromethylphenyl , -CH (OH) -benzo [d] [1,3] dioxazolyl, -CH (OH) - 4-isopropylphenyl or -CH (OH) -3-chloro-4-fluorophenyl; Rº is -CH3; and Rº is H.
[0118] [0118] In yet other preferred embodiments, compounds of Formula | -B are those in which R * is -CH (OH) -4-chlorophenyl, -CH (OH) -3,4- dichlorophenyl, or -CH (OH ) -3-methyl-4-chlorophenyl; Rº is -CH3; and Rº is H or F.
[0119] [0119] In some preferred embodiments, compounds of Formula | -B are those in which R * is -CH (OH) -4-chlorophenyl, -CH (OH) -3,4- dichlorophenyl, -CH (OH) - 3,4-difluorophenyl, -CH (OH) -3-fluoro-4-chlorophenyl, -CH (OH) -3-chloro-4-fluorophenyl, -CH (OH) -3-methyl-4-chlorophenyl, -CH (OH) -3-fluoro-4-trifluoromethylphenyl, - -C (Me) (OH) -4-chlorophenyl, - -C (Me) (OOH) -3,4-dichlorophenyl, - C (Me) (0H) -3,4-difluorophenyl, -C (Me) (OH) -3-fluoro-4-chlorophenyl, -C (Me) (OH) -3-chloro-4-fluorophenyl, -C (Me) (OH) - 3-methyl-4-chlorophenyl or —-C (Me) (OH) -3-fluoro-4-trifluoromethylphenyl; Rº is -CH3; and R5 is H.
[0120] [0120] In other preferred embodiments, compounds of Formula | -B are those in which R * is -CH (OH) -4-chlorophenyl, -CH (OH) -3,4- dichlorophenyl, -CH (OH) - 3-methyl-4-chlorophenyl, -CH (OH) -4-trifluoromethylphenyl, -CH (OH) -4-fluoro-3-trifluoromethylphenyl, -CH (OH) -3-fluoro-4-trifluoromethylphenyl, -CH (OH ) -4-chloro-2- (hydroxymethyl) phenyl; Rº is -CH3; and R is H.
[0121] [0121] In some preferred embodiments, compounds of Formula | -B are those in which R * is -C1-Cçalg-O-aryl; Rº is -NRÓRS ', -NH-O-Rº or -NH-NRÓRS RóéHouF; eRºeR ”are each, independently, H or - Cir-Crealquila.
[0122] [0122] In other preferred embodiments, compounds of Formula | -B are those in which R * is -C-Cálg-O-aryl, Ra is -NH2, -NH-O-CH3 or -NH-NHCH3, and R is H or F.
[0123] [0123] In other preferred embodiments, compounds of Formula | -B are those in which R * is -CH2-0-3- (aminomethyl) phenyl; Rº is -NH>, - NH-O-CH3or -NH-NHCH3; eR it's Hour.
[0124] [0124] In some respects, the present disclosure is directed to compounds of Formula | -B where R * is -C1-Cçealg-S-C1-Cçealquila, Rº is -NRÓRO ”, - NH-O-Rº or -NH -NRºRó '; and Rº and Rº are each, independently, H or -C7- Cçalquila.
[0125] [0125] In some respects, the present disclosure is directed to compounds of Formula | -B where R * is -C1-Cçalg-O-C1-Cçéalquila, Rº is -NRÓRO, - NH-O-Rº or -NH- NRºRó '; and Rº and Rº are each, independently, H or -Cr- Cçalquila.
[0126] [0126] In some preferred embodiments, the present disclosure is directed to compounds of Formula | -C As HO oH À AÀ LO = heteroaryl LL) In E Ré Fe where Rº is -NR6Rº, -NH-O-Rº or -NH -NRºRó; Rº is HouF; and RºeRº are each, independently, H or -Ci-Cealquila. Other preferred modalities are compounds of Formula | -C where Rº is -NRºRº, -NH-O-R $ or -NH-NR $ ÓRó; R is H or F; Rº and RÉ are each, independently, H or -C1- Cçealkyl, and heteroaryl is quinolinyl, substituted quinolinyl, indolyl, substituted indolyl, indazolyl, or substituted indazolyl.
[0127] [0127] Other preferred embodiments are compounds of Formula | -C where R ° is -NH2, -NH-O-CH3 or -NH-NHCH3; and Rº is H or F.
[0128] [0128] Other preferred embodiments are compounds of Formula | -C in which R is —-NH2, -NH-OH, -NH-O-CH3 or -NH-NHCH3; Rº is H or F, Rº and Rº are each, independently, H or -C1-C6 alkyl, and heteroaryl is quinolinyl, substituted quinolinyl, indolyl, substituted indolyl, indazolyl, substituted indazolyl, imidazo [1,2- a] pyridinyl or substituted imidazo [1,2-a] pyridinyl.
[0129] [0129] Other preferred embodiments are compounds of Formula | -C where heteroaryl is (2-amino-3-bromoquinolin-7-yl), (2-amino-3-chloroquinolin-7-yl), - (2-amino -3-fluoroquinolin-7-yl), - (2- (methylamino) - quinolin-7-yl), - (2-
[0130] [0130] Other preferred embodiments are compounds of Formula | -C where heteroaryl is (2-amino-3-bromoquinolin-7-yl), (2-amino-3-chloroquinolin-7-yl), (2-amino- 3-fluoroquinolin-7-yl), (2- (methylamino) quinolin-7-yl), (2-aminoquinolin-7-yl), (indol-6-yl), (indazol-6-yl), and Rº is -NRÓRS, -NH-ORó or -NH- NRÓRó: Rº is H or F; and Rº and RÔ are each, independently, H or -Cx- Cçalquila.
[0131] [0131] Other preferred modalities are compounds of Formula IC in which heteroaryl is quinolinyl, substituted quinolinyl, indolyl, substituted indolyl, indazolyl, substituted indazolyl, imidazo [1,2-a] pyridinyl or imidazo [1,2-a] substituted pyridinyl ; Rº is -NRRÔ, -NH-OR $ or -NH-NRÓRÔ; R is HouF, and Rºó and RÔ are each, independently, H or -C 1 -C; alkyl.
[0132] [0132] Other preferred embodiments are compounds of Formula | -C where heteroaryl is quinolin-7-yl, (2-amino-3-bromoquinolin-7-yl), (2-amino-3-chloroquinolin-7-yl) , (2-amino-3-fluoroquinolin-7-yl), (2- (methylamino) quinolin-7-yl), (2-aminoquinolin-7-yl), 2- (methoxyamino) quinolin-7-yl, ( indol-6-yl), (indazol-6-yl) or (3-methylimidazo [1,2-alpiridine-7yl); Rº is -NRRS, -NH-OR $ or -NH-NR $ ÓRS; RºéHouF; eRóeRó are each, independently, H or -Cr-Cçéalquila.
[0133] [0133] In some preferred embodiments, the present disclosure is directed to compounds of Formula | -D
[0134] [0134] Some modalities of compounds of Formula | -D are those in which Rº is -NRRó ', -NH-O-Rº or -NH-NRR6; Rº is HouF; Rº and R $ are each, independently, H or -C1-Cçéalkyl, and aryl is a mono- or bicyclic-aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, where one or more of the carbon atoms in which the ring is optionally substituted with a halogen atom, a -C1-Cyalkyl group, an amine-substituted -C7-Czalkyl group, a -C17-C3 haloalkyl group, an amine group (ie, - NH2), or a substituted amine group.
[0135] [0135] Other preferred embodiments are compounds of Formula | -D where R ° is -NH2, -NH-O-CH3 or -NH-NHCH3; and Rº is H or F.
[0136] [0136] Other preferred embodiments are compounds of Formula | -D where R ° is —-NH> 2, -NH-OH, -NH-O-CH3 or -NH-NH-CH3; and Rº is H or F, Rº and Rº are each, independently, H or -C1-Cçalquila, and aryl is phenyl or substituted phenyl.
[0137] [0137] Other preferred embodiments are compounds of Formula | -D where aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, -3-fluoro-4-
[0138] [0138] Other preferred embodiments are compounds of Formula | -D where aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, -3-fluoro-4-chlorophenyl, -3-chloro- 4-fluorophenyl, -3-methyl-4-chlorophenyl, 3-fluoro-4-trifluoromethylphenyl or -4-fluoro-3-trifluoromethylphenyl, Rº is -NRºRÔ ”, -NH-OR $ or - NH-NRÓRÔ: R is HouF; eRóeR ”are each, independently, H or -C1- Cçalquila.
[0139] [0139] Still other preferred embodiments are compounds of Formula | -D where aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, -3-fluoro-4-chlorophenyl, -3-chlorine -4-fluorophenyl, - 3-methyl-4-chlorophenyl or -3-fluoro-4-trifluoromethylphenyl; R ° is -NH2, -NH-O-CH3 or -NH-NHCH3; and Rº is HouF.
[0140] [0140] Other preferred embodiments are compounds of Formula | -D where aryl is -4-chlorophenyl, -4-chloro-2- (hydroxymethyl) phenyl, -3,4-dichlorophenyl,-3,4-difluorophenyl, -3 -fluoro-4-chlorophenyl, -3-methyl-4-chlorophenyl, -3-fluoro-4-trifluoromethylphenyl, -4-trifluoromethylphenyl, - 4- (trifluoromethoxy) phenyl, -4-fluoro-3-trifluoromethylphenyl, -benzo [d] [1,3] dioxazolyl, - 4-isopropylphenyl or -3-chloro-4-fluorophenyl; R ° is -NH2, -NH-O-CH3 or -NH-NHCH3; and R is H or F.
[0141] [0141] In some preferred modalities, the present disclosure is directed to compounds of Formula | -E NO "and 8 sCHs Rº Pá AX
[0142] [0142] Other preferred embodiments are compounds of Formula I-E where R ° is -NH2, -NHCH3, -NH-O-CH3 or -NH-NHCH3; and R is H or F.
[0143] [0143] In some preferred modalities, the present disclosure is directed to compounds of the Formula | -F YO 2 Sen
[0144] [0144] Other preferred embodiments are compounds of Formula | -F where R ° is —-NH> 2, -NHCH3, -NH-O-CH3 or -NH-NHCH3; and Rº is H or F.
[0145] [0145] In some preferred embodiments, the present disclosure is directed to compounds of Formula | -G NO "and SicH, the ER == HR -G where R * is -Co-Cçalg-C1-Cçalquila, -Co-Cealg -C1-Céhaloalkyl, -C1- Cçealg-O-C1-Cçalquila, -C1-Cealg-S-C1-Cçéalquila, -C1-Cçealg-arila, -C1-Cealg-O-arila, -
[0146] [0146] In some embodiments, compounds of the general formula 1-G are those in which R * is -Ci-Cçalg-aryl or -C1-Cç alg-O-heteroaryl; and R º is H or F.
[0147] [0147] In some embodiments, compounds of the general formula 1-G are those in which R * is -C1-Ceéalg-aryl and R is H or F. In some embodiments, compounds of general formula IG are those in which R * is -Ci-Cçalg-aryl in which the aryl is a mono- or bicyclic-aromatic hydrocarbon ring structure having 6 or 10 atoms of carbon in the ring, where one or more of the carbon atoms in which the ring is optionally substituted with a halogen atom, a -C1-C3alkyl group, an amino substituted alkyl group, a -C7-Ci3haloalkyl group, a group amine (i.e., -NH2), or a substituted amine group; and Rº is H or F.
[0148] [0148] In some embodiments, compounds of the general formula 1-G are those in which R * is -C1-Cçéalg-O-heteroaryl and Rº is H or F.
[0149] [0149] In other preferred modalities, the present disclosure is directed to compounds of the Formula | -H VS & Sen, - N o zT Ri
[0150] [0150] Some preferred embodiments are compounds of Formula IH in which R 'represents -C-Cçalg-OC-Cçalquila, -C7-Céalg-S-Cy- Cçealquila, -C1-Cçealg-arila, -Co-Cçealg-heteroarila , -C1-Cçealg-O-heteroaryl -C1-Cçealg-S-heteroaryl, or -C1-Cealg-NH-heteroaryl; R is H or F; And Rº is He RÓ is methyl.
[0151] [0151] In some embodiments, compounds of the general formula | -H are those in which R * is -C1-Ceéalg-aryl or -C1-Cçé alg-O-heteroaryl; and R is H or F; and Rº and Rº are each, independently, H or -C1-Cçalquila.
[0152] [0152] In some preferred embodiments, compounds of Formula | -H are those in which R * is -C-Cçalg-aryl; R is H or F; and Rº and RÔ are each, independently, H or -C17-Cçéalquila. In some embodiments, compounds of Formula | -H are those in which R1 is -C1 -C6 alg-aryl in which the aryl is a mono- or bicyclic-aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring , wherein one or more of the carbon atoms in which the ring is optionally substituted with a halogen atom, an -C1-C3alkyl group substituted with an amine -C1-C3zalkyl group, an -C1-C3haloalkyl group, an amine group (i.e., -NH2), or a substituted amino group; R is H or F; and Rº and Rº are each, independently, H or -C1- Cçalquila.
[0153] [0153] In some preferred embodiments, compounds of Formula | -H are those in which R * is -C1-Cçalg-O-heteroaryl; R is H or F; eRº and R $ are each, independently, H or -C1-Cçalquila.
[0154] [0154] In other preferred modalities, the present disclosure is directed to compounds of Formula | -)
[0155] [0155] Some preferred modalities are compounds of Formula | -) | where R * represents -C1-Cçalg-O-C1-Cçalquila, -C1i-Cealg-S-C1- Cçealkyl, -C1-Cçealg-arila, -Co-Cçealg-heteroaryl, -C1-Cçealg-O-heteroarila - C1-Cçealg-S-heteroaryl, or -C1-Cealg-NH-heteroaryl; R is H or F; and Rº is methyl.
[0156] [0156] In some embodiments, compounds of the general formula | -) are those in which R * is -C1-Cçalg-aryl or -C1-C6 alg-O-heteroaryl; and R º is H or F; and Rº and Rº are each, independently, H or -Cr-Cçalquila.
[0157] [0157] In some preferred embodiments, compounds of Formula | -) are those in which R * is -C1-Cçéalg-arila; R is H or F; and Rº and Rº are each, independently, H or -C1r-Ceéalquila. In some embodiments, compounds of Formula | -) are those in which R * is -C1 -C6 alg-aryl where the aryl is a mono- or bicyclic-aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, in which one or more of the carbon atoms in which the ring is optionally substituted with a halogen atom, an amine-substituted -C1-C3alkyl group, a -C1-C3haloalkyl group, a amine (i.e., -NH2), or a substituted amino group; R is H or F; and Rs; and Rg are each, independently, H or -C1- Cálquila.
[0158] [0158] In some preferred embodiments, compounds of Formula | -] are those in which R * is -C1-Cealg-O-heteroaryl; Rº is Hou F; and Rô and Rº 'are each, independently, H or -C-Cçalquila.
[0159] [0159] References to the Formula | of this document also refer to Formulas IA, IB, IC, ID, IE, IF, IG, IH and l).
[0160] [0160] Stereoisomers of compounds of Formula | are also covered by this disclosure. Accordingly, the disclosure covers all constitutional stereoisomers and isomers of any compound disclosed or claimed herein, including all enantiomers and diastereomers.
[0161] [0161] The pharmaceutically acceptable salts and solvates of the compounds of Formula | are also within the scope of the disclosure.
[0162] [0162] Isotopic variants of compounds of Formula | are also covered by this disclosure.
[0163] [0163] The pharmaceutical compositions in question are typically formulated to provide a therapeutically effective amount of a compound of the present disclosure as an active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. Where desired, pharmaceutical compositions contain pharmaceutically acceptable salt and / or coordination complex and one or more pharmaceutically acceptable excipients, carriers, including diluents and inert solid fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
[0164] [0164] The pharmaceutical compositions in question can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions. Where desired, the one or more compounds of the invention and other agents can be mixed in one preparation or both components can be formulated in separate preparations for use in combination separately or at the same time.
[0165] [0165] In some embodiments, the concentration of one or more compounds supplied in the pharmaceutical compositions of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% , 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3 %, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0, 1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009% , 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% (or a number in the range defined by and including any two numbers above) p / p, p / v or v / v.
[0166] [0166] In some embodiments, the concentration of one or more compounds of the invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19, 50%, 19.25%, 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25% 15%, 14.45%, 14.50%, 14.25% 14%, 13.75 %, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25% 8 %, 7.75%, 7.50%, 7.25%, T%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5, 25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50 %, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0, 5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0, 04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% (or a number in the range defined by and including any two numbers above) p / p, p / v or v / v.
[0167] [0167] In some embodiments, the concentration of one or more compounds of the invention is in the range of approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0 , 02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0 , 07% to approximately 24%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0 , 2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0 , 7% to approximately 15%, approximately 0.8% to approximately 14%, apr approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w / w, w / v or v / v.
[0168] [0168] In some embodiments, the concentration of one or more compounds of the invention is in the range of approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9%, w / w, w / v or v / v.
[0169] [0169] In some embodiments, the amount of one or more compounds of the invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 9, 8.0 9, 7.59, 7, 0 g, 6.5 g, 6.0 9, 5.5 g, 5.0 g, 4.5 g, 4.0 9, 3.5 g, 3.0 g, 2.59, 2.0 9, 1.59, 1.09, 0.95 g, 0.9 g, 0.85 9, 0.8 g, 0.75 g, 0.7 g, 0.65 9, 0.6 g, 0.55 g, 0.59, 0.459.0.49, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 9, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 9, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 9, 0.007 g, 0.006 g, 0.005 g, 0.004 9, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 9, 0.0007 g, 0.0006 g, 0.0005 9, 0.0004 g, 0.0003 g, 0.0002 g or 0.0001 g (or a number in the range defined by and including any two numbers above).
[0170] [0170] In some embodiments, the amount of one or more compounds of the invention is greater than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 9, 0.0005 g, 0.0006 g, 0 .0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 9, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0 .0055 g, 0.006 9, 0.0065 9, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.0085 g, 0.009 g, 0.0095 9, 0.01 g , 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 9, 0.055 9, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 9, 0.15 g, 0.2 g, 0.25 9, 0.3 g, 0, 35 9, 0.4 9, 0.45 g, 0.5 9, 0.55 9, 0.6 9, 0.65 9.0.79, 0.75 9, 0.8 g 9, 0, 85 g, 0.9 g, 0.959, 1 g, 1.5 g, 2 g, 2.5, 3 9, 3.5, 49, 4.59, 59, 5.5 9, 6.5 9, 6 9, 6.5 9, 7 9, 7.5 9, 8 g, 8.5 9, 9 g, 9.5 g or 10 g (or a number in the range defined by and including any two numbers above).
[0171] [0171] In some embodiments, the amount of one or more compounds of the invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 9, 0.005-7 g, 0.01-6 g , 0.05-5 g, 0.1 -4 g, 0.5-49g or 1-3 9.
[0172] [0172] The compounds according to the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages of 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg per day and from 40 mg per day are examples of dosages that can be used. An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated and the preference and experience of the attending physician.
[0173] [0173] A pharmaceutical composition of the invention typically contains an active ingredient (i.e., a compound of the disclosure) of the present invention or a pharmaceutically acceptable salt and / or coordination complex thereof, and one or more excipients, pharmaceutically acceptable carriers, including , but are not limited to, inert solid fillers and diluents, thinners, sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
[0174] [0174] Exemplary non-limiting pharmaceutical compositions and methods for preparing them are described below.
[0175] [0175] In some embodiments, the invention provides a pharmaceutical composition for oral administration containing a compound of the invention and a pharmaceutical excipient suitable for oral administration.
[0176] [0176] In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of a compound of the invention; optionally (ii) an effective amount of a second agent; and (ii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition also contains: (iv) an effective amount of a third agent.
[0177] [0177] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules,
[0178] [0178] This invention also covers anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds. For example, water can be added (for example, 5%) in the pharmaceutical arts as a means of simulating long-term storage, in order to determine characteristics such as the shelf life or the stability of the formulations over time. The anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture ingredients and conditions of low humidity or low humidity. The pharmaceutical compositions and dosage forms of the invention that contain lactose can be made anhydrous if substantial contact with moisture and / or moisture is expected during manufacture, packaging and / or storage. An anhydrous pharmaceutical composition can be prepared and stored so that its anhydrous nature is maintained. Therefore, anhydrous compositions can be packaged using known materials to prevent exposure to water, so that they can be included in suitable form kits. Examples of suitable packaging include, but are not limited to, hermetically sealed films, plastics or the like, unit dose containers, blister packs and strip packs.
[0179] [0179] An active ingredient can be combined in an intimate mixture with a pharmaceutical carrier according to conventional pharmaceutical composition techniques. The carrier can take a wide variety of forms, depending on the form of preparation desired for administration. In preparing compositions for an oral dosage form, any usual pharmaceutical medium can be employed as a carrier, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, dyes and the like in the case of liquid oral preparations (such as suspensions, solutions and elixirs) or aerosols; or vehicles such as starches, sugars, microcrystalline cellulose, thinners, granulating agents, lubricants, binders and disintegrating agents can be used in the case of solid oral preparations, in some modalities without employing the use of lactose. For example, suitable carriers include powders, capsules and tablets, with solid oral preparations. If desired, the tablets can be coated by standard aqueous or non-aqueous techniques.
[0180] [0180] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as acacia,
[0181] [0181] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, powdered cellulose , dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch and mixtures thereof.
[0182] [0182] Disintegrants can be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. An excess disintegrator can produce pills that can disintegrate in the bottle. Very little can be insufficient for disintegration and thus change the rate and extent of release of the active ingredient (s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too small nor too much to adversely alter the release of the active ingredient (s) can be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used can vary based on the type of formulation and mode of administration, and can be easily discernible to those skilled in the art. About 0.5 to about 15 weight percent disintegrant, or about 1 to about 5 weight percent disintegrant, can be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, potassium polacrylin, sodium starch glycolate , potato or tapioca starch, other starches, pregelatinized starches, other starches, clays, other algae, other celluloses, gums or mixtures thereof.
[0183] [0183] Lubricants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol , other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (eg, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soy oil ), zinc stearate, ethyl oleate, ethyl laureate, agar or and mixtures thereof. Additional lubricants include, for example, a silica silica gel, a coagulated synthetic silica aerosol or mixtures thereof. A lubricant can optionally be added, in an amount less than about 1 weight percent of the pharmaceutical composition.
[0184] [0184] When aqueous suspensions and / or elixirs for oral administration are desired, the active ingredient can be combined with various sweetening or flavoring agents, dyes or dyes and, if desired, emulsifying and / or suspending agents, together with diluents such as water , ethanol, propylene glycol, glycerin and various combinations thereof.
[0185] [0185] The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thus provide a sustained action for a longer period. For example, a time-delaying material, such as glyceryl monostearate or glyceryl distearate, can be employed. Formulations for oral use can also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the ingredient The active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
[0186] [0186] The surfactant that can be used to form pharmaceutical compositions and dosage forms of the invention includes, but is not limited to, hydrophilic surfactants, lipophilic surfactants and mixtures thereof. That is, a mixture of hydrophilic surfactants can be employed, a mixture of lipophilic surfactants can be employed or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant.
[0187] [0187] A suitable hydrophilic surfactant can generally have an HLB value of at least 10, while suitable lipophilic surfactants can generally have an HLB value of 10 or less. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of compounds nonionic amphiphilic is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic and have greater solubility in aqueous solutions.
[0188] [0188] Hydrophilic surfactants are generally considered those compounds with an HLB value greater than about 10, as well as anionic, cationic or zwitterionic compounds for which the HLB scale is generally not applicable. Likewise, lipophilic (ie hydrophobic) surfactants are compounds with an HLB value equal to or less than about
[0189] [0189] Hydrophilic surfactants can be ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides and polypeptides; glyceride derivatives of amino acids,
[0190] [0190] Within the group mentioned above, ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and their derivatives; ester salts of carnitine fatty acids; alkylsulfate salts; fatty acid salts; sodium docusate; acylactylates; esters of mono- and di-acetylated tartaric acid of mono- and di-glycerides; succinylated mono- and di-glycerides; esters of citric acid of mono- and di-glycerides; and their mixtures.
[0191] [0191] Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol |, lysophosphatidic acid, lysophosphatidylserine, PEG -fosfatidiletanolamina PVP -fosfatidilethanolamina, lactylic esters fatty acids, stearoyl-2-lactylate, stearoyl-lactylate, succinylated monodglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citric acid esters of mono / diglycerides, colilsarcosine, caproate, caprylate, caprate, caprate, lavertate, caprate of sodium oleate oleate lineate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauryl carnitines, palmitoyl carnitines, myristoyl carnitines and salts and mixtures thereof.
[0192] [0192] Non-ionic hydrophilic surfactants may include, but are not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides;
[0193] [0193] Other non-ionic hydrophilic surfactants include, without limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, oleate PEG-12, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG distearate -32, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate , PEG-20 glyceryl stearate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-30 glyceryl laurate, laurate glycerol oil, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, hydrogenated PEG-40 castor oil, hydrogenated PEG-60 castor oil, P corn oil EG-60, PEG-6 caprate / caprylate glycerides, PEG-8 caprate / caprylate glycerides, polyglyceryl laurate 10, PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 soy sterol, PEG-30 trioleate PEG-20, PEG-40 sorbitan oleate, P EG-80 sorbitan laurate, polysorbate up to 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 steric ether, POE-20 stearyl ester, PEG-100 tocopheryl succinate, PEG-24 cholesterol, polyglyceryl cholesterol, Tween 40, Tween 60, sucrose monostearate, sucrose mono laurate, sucrose monopalmitate, PEG 10 series -100 nonyl phenol, PEG series 15-100 octylphenol and poloxamers.
[0194] [0194] Suitable lipophilic surfactants include, by way of example only: fatty alcohols; esters of glycerol fatty acids; esters of acetylated glycerol fatty acids; fatty acid esters with low alcohol content; propylene glycol fatty acid esters; esters of sorbitan fatty acids; esters of polyethylene glycol sorbitan fatty acids; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; alkyl ethers of polyethylene glycol; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins / vitamin derivatives; and their mixtures. Within this group, preferred lipophilic surfactants include esters of glycerol fatty acids, esters of propylene glycol fatty acids and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils , hydrogenated vegetable oils and triglycerides.
[0195] [0195] In one embodiment, the composition may include a solubilizer to ensure good solubilization and / or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This can be especially important for compositions for non-oral use, for example, compositions for injection. A solubilizer can also be added to increase the solubility of the hydrophilic drug and / or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.
[0196] [0196] Examples of suitable solubilizers include, but are not limited to, alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanedioles and their isomers, glycerol, pentaerythritol, sorbitol, mannitol, dimethyl transcutol , polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropylmethylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; polyethylene glycols ethers with an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol (glycofurol) or methoxy PEG ether; amides and other nitrogen-containing compounds, such as 2-pyrrolidone, 2-piperidone, e-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, “dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, propylene glycol diacetate and propylene glycol diacetate caprolactone and its isomers, ôó-valprolactone and its isomers, O-valprolactone and isomers thereof, ô-valprolactone p-butyrolactone and its isomers; and other solubilizers known in the art, such as dimethyl acetamide, —dimethyl isosorbide, N-methylpyrrolidones, “monooctanoin, monoethyl diethylene glycol ether and water.
[0197] [0197] Mixtures of solubilizers can also be used. Examples include, but are not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl and ethylene glycol cyclodextrins, ethanol, ethanol, ethanol, ethanol, ethanol dimethyl. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofuro! and propylene glycol.
[0198] [0198] The amount of solubilizer that can be included is not particularly limited. The amount of a particular solubilizer can be limited to a bioacceptable amount, which can be easily determined by one skilled in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example, to maximize the concentration of the drug, with the excess solubilizer removed before supplying the composition to a subject using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer can be in the weight ratio of 10%, 25%, 50%), 100% or even about 200%> by weight, based on the combined weight of the drug and other excipients. If desired, very small amounts of solubilizer can also be used, such as 5%>, 2%>, 1%) or even less. Typically, the solubilizer can be present in an amount of about 1% to about 100%, more typically about 5% to about 25% by weight.
[0199] [0199] The composition may further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, unpackers, antifoaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents,
[0200] [0200] In addition, an acid or a base can be incorporated into the composition to facilitate processing, improve stability or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, aluminum and magnesium silicate, synthetic aluminum silicate , synthetic hydrocalcite, aluminum and magnesium hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris (hydroxymethyl) aminomethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids , formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenyl sulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate and sodium dihydrogen phosphate, can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals and the like. The example may include, but is not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.
[0201] [0201] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenyl sulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic, toluenesulfonic acid, uric acid and the like.
[0202] [0202] In some embodiments, the invention provides a pharmaceutical composition for injection containing a compound of the present invention and a pharmaceutical excipient suitable for injection. The components and amounts of agents in the compositions are as described herein.
[0203] [0203] Forms in which the new compositions of the present invention can be incorporated for administration by injection include aqueous or oily suspensions or emulsions, with sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs , mannitol, dextrose, or a sterile aqueous solution and similar pharmaceutical carriers.
[0204] [0204] Aqueous saline solutions are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol and the like (and mixtures thereof),
[0205] [0205] Sterile injectable solutions are prepared by incorporating the compound of the present invention in the required amount in the appropriate solvent with various other ingredients as listed above, as needed, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile carrier that contains the basic dispersion medium and the other necessary ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are vacuum drying and freeze-drying techniques that produce a powder of the active ingredient plus any desired additional ingredient from a previously sterile filtered solution.
[0206] [0206] In some embodiments, the invention provides a pharmaceutical composition for transdermal administration containing a compound of the present invention and a pharmaceutical excipient suitable for transdermal administration.
[0207] [0207] The compositions of the present invention can be formulated into preparations in solid, semi-solid or liquid forms suitable for local or topical administration, such as gels, water-soluble gels, creams, lotions, suspensions, foams, powders, pastes, ointments , solutions, oils, pastes,
[0208] [0208] Pharmaceutical compositions can also comprise suitable carriers or excipients in solid or gel phase, which are compounds that allow greater penetration or assist in the administration of therapeutic molecules through the permeability barrier of the stratum corneum of the skin. There are many of these penetration-enhancing molecules known to those skilled in the topic formulation technique.
[0209] [0209] Examples of such carriers and excipients include, but are not limited to, humectants (eg, urea), glycols (eg, propylene glycol), alcohols (eg, ethanol), fatty acids (eg, oleic acid), surfactants (eg isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (eg menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers, such as polyethylene glycols.
[0210] [0210] Another exemplary formulation for use in the methods of the present invention employs transdermal delivery devices ("adhesives"). Such transdermal patches can be used to provide continuous or batch infusion of a compound of the present invention in controlled amounts, with or without another agent.
[0211] [0211] The construction and use of transdermal patches for the administration of pharmaceutical agents is well known in the art. See, for example, Pat. U.S. 5,023,252, 4,992,445 and 5,001,139. Such plasters can be built for continuous, pulsating or on demand delivery of pharmaceutical agents.
[0212] [0212] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions can contain suitable pharmaceutically acceptable excipients, as described above. Preferably, the compositions are administered via the oral or nasal airway for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents can be nebulized by the use of inert gases. The nebulized solutions can be inhaled directly from the nebulizer device or the nebulizer device can be connected to a face mask tent or a breathing apparatus with intermittent positive pressure. Solution, suspension or powder compositions can be administered, preferably orally or nasally, from devices that deliver the formulation appropriately.
[0213] [0213] Pharmaceutical compositions may also be prepared from the compositions described herein and from one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural or intraspinal administration. Preparations for such pharmaceutical compositions are well known in the art. See for example, Anderson, Philip O .; Knoben, James E .; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-S econd Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference here in their entirety.
[0214] [0214] The administration of the compounds or pharmaceutical composition of the present invention can be carried out by any method that allows the administration of the compounds at the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (eg, transdermal application), rectal administration, via local catheter or stent administration or by inhalation. The compounds can also be administered intra-adiposally or intrathecally.
[0215] [0215] The amount of the compound administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg of body weight per day, preferably about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human being, this would amount to about 0.05 to 7 g / day, preferably about 0.05 to about 2.5 g / day. In some cases, dosage levels below the lower limit of the aforementioned range may be more than adequate, while in other cases even higher doses may be used without causing any harmful side effects, for example, by dividing these larger doses into several doses small for administration throughout the process throughout the day.
[0216] [0216] In some embodiments, a compound of the invention is administered in a single dose.
[0217] [0217] Usually, this administration will be by injection, for example, intravenous injection, to introduce the agent quickly. However, other routes can be used as appropriate. A single dose of a compound of the invention can also be used for the treatment of an acute condition.
[0218] [0218] In some embodiments, a compound of the invention is administered in multiple doses. The dosage can be once, twice, three times, four times, five times, six times or more than six times a day. Dosing can occur about once a month, once every two weeks, once a week or once every two days. In another embodiment, a compound of the invention and another agent are administered together about once a day to about 6 times a day. In another embodiment, administration of a compound of the invention and an agent continues for less than about 7 days. In yet another modality, administration continues for more than about 6, 10, 14, 28 days, two months, six months or a year. In some cases, continuous dosing is achieved and maintained for as long as necessary.
[0219] [0219] Administration of the compounds of the invention can continue as long as necessary. In some embodiments, a compound of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14 or 28 days. In some embodiments, a compound of the invention is administered for less than 28, 14, 7.6, 5, 4, 3, 2 or 1 day. In some embodiments, a compound of the invention is administered chronically on a continuous basis, for example, for the treatment of chronic effects.
[0220] [0220] An effective amount of a compound of the invention can be administered in single or multiple doses by any of the accepted modes of administration of agents with similar uses, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, by intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically or as an inhalant.
[0221] [0221] The compositions of the invention can also be applied via an impregnated or coated device, such as a stent, for example, or a cylindrical polymer inserted in the artery. Such a method of administration can, for example, assist in preventing or improving restenosis after procedures such as balloon angioplasty. Without being bound by theory, the compounds of the invention can slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall that contribute to restenosis. A compound of the invention can be administered, for example, by local administration from the stent struts, from a stent, from grafts, or from the cover or sheath of a stent. In some embodiments, a compound of the invention is mixed with a matrix. This matrix can be a polymeric matrix and can serve to bind the compound to the stent. Polymeric matrices suitable for such use include, for example, lactone-based polyesters or copolyesters, such as polylactide, polycaprolactoglycolide, polyiortoesters, polyanidides, polyamino acids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (for example, PEO-PL ); polydimethylsiloxane, poly (ethylene vinylacetate), acrylate-based polymers or copolymers (eg, polyhydroxyethyl methyl methacrylate, polyvinyl pyrrolidinone), fluorinated polymers, such as polytetrafluoroethylene and cellulose esters. Suitable matrices may not degrade or degrade over time, releasing the compound or compounds. The compounds of the invention can be applied to the surface of the stent by various methods, such as dip / spin coating, spray coating, dip coating and / or brush coating. The compounds can be applied in a solvent and the solvent can evaporate, thereby forming a compound layer on the stent. Alternatively, the compound can be located in the body of the stent or graft,
[0222] [0222] A variety of stent devices that can be used as described are disclosed, for example, in the following references, all of which are incorporated herein by reference: Pat. No. 5451233; Pat. No. 5040548; Pat. No. 5061273; Pat. No. 5496346; Pat. No. 5292331; Pat. No. 5674278; Pat. No. 3657744; Pat. No. 4,739,762; Pat. No. 5195984; Pat. U.S. No. 5292331; Pat. No. 5674278; Pat. No. 5,879,382; Pat. No. 6344053.
[0223] [0223] The compounds of the invention can be administered in dosages. It is known in the art, due to the intersubjective variability in the pharmacokinetics of the compound, it is necessary to individualize the dosage regimen for the ideal therapy. The dosage of a compound of the invention can be found by routine experimentation in the light of the present disclosure.
[0224] [0224] When a compound of the invention is administered in a composition comprising one or more agents, and the agent has a shorter half-life than the compound of the unit dose forms of the agent and the compound of the invention can be adjusted in accordance.
[0225] [0225] The pharmaceutical composition in question may, for example, be in a form suitable for oral administration as a tablet, capsule, tablet, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition can be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
[0226] [0226] Exemplary parenteral administration forms include solutions or suspensions of active compound in sterile aqueous solutions, for example, aqueous solutions of propylene glycol or dextrose. Such dosage forms can be suitably buffered, if desired.
[0227] [0227] The method typically comprises administering to a subject a therapeutically effective amount of a compound of the invention. The therapeutically effective amount of the subject's compound combination can vary depending on the intended application (in vitro or in vivo) or the individual and the disease condition being treated, for example, the subject's weight and age, the severity of the condition disease, the mode of administration and the like, which can be easily determined by one skilled in the art. The term also applies to a dose that will induce a specific response in the target cells, for example, reduced proliferation or down regulation of the activity of a target protein. The specific dose will vary according to the specific compounds chosen, the dosage regimen to be followed, whether it is administered in combination with other compounds, the time of administration, the tissue in which it is administered and the physical delivery system in which it is administered . accomplished.
[0228] [0228] As used herein, the term "ICs9" refers to the semi-maximum inhibitory concentration of an inhibitor in inhibiting biological or biochemical function. This quantitative measure indicates how much of a specific inhibitor is needed to inhibit a given biological process (or component of a process, that is, an enzyme, cell, cell receptor or microorganism) in half. In other words, it is the semi-maximum inhibitory concentration (IC) (50%) of a substance (50% CI or IC50). EC50 refers to the plasma concentration necessary to obtain 50%> of a maximum effect in vivo.
[0229] [0229] In some embodiments, the methods in question use a PRMT5 inhibitor with an IC50 value of approximately or less than a predetermined value, as determined in an in vitro assay. In some embodiments, the PRMTB5 inhibitor inhibits PRMT5 a with an IC50 value of about 1 nM or less, 2 nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or less, 30 nM or less, 40 nM or less, 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM or less, 150 nM or less, 160 nM or less, 170 nM or less, 180 nM or less, 190 nM or less, 200 nM or less, 225 nM or less, 250 nM or less, 275 nM or less, 300 nM or less, 325 nM or less, 350 nM or less, 375 nM or less, 400 nM or less, 425 nM or less, 450 nM or less, 475 nM or less, 500 nM or less, 550 nM or less, 600 nM or less, 650 nM or less, 700 nM or less, 750 nM or less, 800 nM or less, 850 nM or less, 900 nM or less, 950 nM or less, 1 µM or less, 1.1 µM or less, 1.2 one µM or less, 1.3 µM or less, 1.4 µM or less, 1.5 µM or less, 1.6 µM or less, 1.7 µM or less, 1.8 µM or less, 1.9 µM or less, 2 UuM or less, 5 UM or less, 10 µM or less, 15 µM or less, 20 µM or less, 25 µM or less, 30 µM or less, 40 µM or less, 50 µM, 60 µM, 70 µM, 80 µM, 90 µM, 100 µM, 200 CU, 300 CU, 400 CU or 500 CU, or less (or a number in the range defined by and including any two numbers above).
[0230] [0230] In some embodiments, the PRMT5 inhibitor selectively inhibits PRMT5 a with an IC50 value that is at least 2, 3, 4,5,6,7, 8, 9, 10, 15, 20, 25, 30 , 35, 40, 45, 50, 100 or 1000 times less (or a number in the range defined by and including any two numbers above) than your IC50 value relative to one, two or three other PRMTs.
[0231] [0231] In some embodiments, the PRMT5 inhibitor selectively inhibits PRMT5 a with an IC50 value less than about 1 nM, 2 nM, nM, 7 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM , 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 120 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 225 NM, 250 nM, 250 nM, 275 nM, 300 nM, 325 nM, 350 nM, 375 nM, 400 nM, 425 nM, 450 nM, 475 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 800 NM, 850 nM, 900 nM, 950 nM, 1 µM, 1.1 µM, 1.2 µM, 1.3 µM, 1.4 µM, 1.5 µM, 1.6 µM, 1.7 µM, 1.8 µM, 1.9 μm, 2 μm, 5 μm, 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 200 μm, 300 µM, 400 µM or 500 CU (or in the range defined by and including any two numbers above), and said ICs9 value is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100 or 1000 times less (or a number in the range defined by and including any two numbers above) than your IC50 value in relation to one, two or other three of PRMTs.
[0232] [0232] The methods in question are useful for the treatment of a disease condition associated with PRMT5. Any disease condition that directly or indirectly results in an abnormal PRMT5 activity or expression level may be an intended disease condition.
[0233] [0233] Different disease conditions associated with PRMT5 have been reported. PRMTS5 has been implicated, for example, in a variety of human cancers, as well as in various hemoglobinopathies.
[0234] [0234] Non-limiting examples of such conditions include, but are not limited to, Acanthoma, Acinic cell carcinoma, Acoustic neuroma, Acent lentiginous melanoma, Acrospiroma, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute lymphocytic leukemia, Acute leukemia leukemia acute, Leukemia acute, Leukemia acute with maturation, acute myeloid leukemia of dendritic cells, acute myeloid leukemia, acute myeloid leukemia, acute promyelocytic leukemia, adamantinoma, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adrenocortical cell carcinoma, adrenocortical leukemia , AIDS-related cancers, AIDS-related lymphoma, alveolar soft tissue sarcoma, ameloblastic fibroma, anal cancer, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, Angiomyolipoma, Angiosarcoma, appendix cancer, Astrocytoma, Atypical teratoid rabatoid tumor , Basal cell carcinoma, Basal carcinoma, B cell leukemia, B cell lymphoma, Bellini duct carcinoma, bile duct cancer, bladder cancer, blastoma, Bone cancer, Bone tumor, Brain stem glioma, Brain tumor, Breast cancer , Brenner's tumor, Bronchial tumor, Bronchioloalveolar carcinoma, Brown tumor, Burkitt's lymphoma, Cancer of unknown primary site, carcinoid tumor, carcinoma, carcinoma in situ, carcinoma of the penis, carcinoma of unknown primary site, carcinosarcoma, disease of
[0235] [0235] In some modalities, the referred method is to treat a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema and scleroderma, diabetes, retinopathy diabetic, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreas, prostate, colon and epidermoid cancer.
[0236] [0236] In some modalities, this method is to treat a disease or disorder selected from breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, cervical cancer, cervical cancer, leukemia, such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myeloid leukemia (AML), chronic myeloid leukemia (CML) , chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid cancer or hemoglobinopathies such as b-thalassemia and sickle cell disease (SCD).
[0237] [0237] In other modalities, the referred method is to treat a disease selected from breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer or cervical cancer.
[0238] [0238] In other modalities, this method is to treat a disease or disorder selected from among leukemia, such as acute myeloid leukemia
[0239] [0239] In still other modalities, the referred method is to treat a disease selected from CDKN2A deletion cancers; 9P deletion cancers; cancers of MTAP deletion; glioblastoma, NSCLC, head and neck cancer, bladder cancer or hepatocellular carcinoma.
[0240] [0240] The compounds of the disclosure, as well as the pharmaceutical compositions that comprise them, can be administered to treat any of the described diseases, alone or in combination with medical therapy. Medical therapies include, for example, surgery and radiation therapy (for example, gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, systemic radioactive isotopes).
[0241] [0241] In other respects, the compounds of the disclosure, as well as the pharmaceutical compositions that comprise them, can be administered to treat any of the described diseases, alone or in combination with one or more other agents.
[0242] [0242] In other methods, the compounds of the disclosure, as well as the pharmaceutical compositions that comprise them, can be administered in combination with agonists of nuclear receptor agents.
[0243] [0243] In other methods, the compounds of the disclosure, as well as the pharmaceutical compositions that comprise them, can be administered in combination with nuclear receptor agent antagonites.
[0244] [0244] In other methods, the compounds of the disclosure, as well as the pharmaceutical compositions that comprise them, can be administered in combination with an antiproliferative agent.
[0245] [0245] In other respects, the compounds of the disclosure, as well as the pharmaceutical compositions that comprise them, can be administered to treat any of the diseases described, alone or in combination with one or more other chemotherapeutic agents. Examples of other chemotherapeutic agents include, for example, abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, all-trans retinoic acid, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bendamustine, bevacizsulfan, intravenous, busbizsulfan, intravenously calusterone, capecitabine, carboplatin, carmustine, —cetuximab, chlorambucil, cisplatinay cladribinay clofarabine, cyclophosphamide, cytarabine, y dacarbazine, dactinomycin, dalteparin sodium, dasatinib, - daunorubin, duninodine, dunidine, dunidine, , erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinibine, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotinamine, lapatinate, irinotaminone , leuprolide acetate, levamisole, lom ustine, mecloretamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalene, mitomycin C, mitotolandine, nitoxantrone, nitoxantrone, nitoxantrone - pamidronate, - panobinostat, - panitumumab, pegasparroxamine, pegaspargamide, pegfilastatin, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinoxin, sunitinoxide tiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine,
[0246] [0246] In other respects, the other agent is a therapeutic agent that targets an epigenetic regulator. Examples of epigenetic regulatory agents include, for example, bromodomain inhibitors, histone lysine methyltransferases, histone arginine methyltransferases, histone demethylases, histone deacetylases, histone acetylases and DNA methyltransferases, as well as any combination thereof. Histone deacetylase inhibitors are preferred in some ways and include, for example, vorinostat.
[0247] [0247] In other methods, in which the disease to be treated is cancer or other proliferative disease, the compounds of the disclosure, as well as the pharmaceutical compositions that comprise them, can be administered in combination with targeted therapy agents. Target therapies include, for example, J AK kinase inhibitors (eg, Ruxolitinib), PI3 kinase inhibitors (including selective and broad-spectrum PI3K delta inhibitors), MEK inhibitors, cyclin-dependent kinase inhibitors (eg CDKA4 / 6 inhibitors), BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (eg, bortezomib, carfilzomib), HDAC inhibitors (eg, panobinostat, vorinostat), DNA methyl transferase inhibitors, dexamethasone , members of the bromine family and terminal terminals, BTK inhibitors (eg, ibrutinib, acalabrutinib), BCL2 inhibitors (eg, venetoclax), MCL1 inhibitors, PARP inhibitors, FLT3 inhibitors and LSD1 inhibitors, as well as any combination thereof.
[0248] [0248] In other methods, in which the disease to be treated is cancer or other proliferative disease, the compounds of the disclosure, as well as the pharmaceutical compositions that comprise them, can be administered in combination with immune checkpoint inhibiting agents. Immune checkpoint inhibitors include, for example, PD-1 inhibitors, for example, an anti-PD-1 monoclonal antibody. Examples of anti-PD-1 monoclonal antibodies include, for example, nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDROO1 and AMP-224, as well as combinations thereof. In some ways, the anti-PD1 antibody is nivolumab. In some ways, the anti-PD1 antibody is pembrolizumab. In some respects, the immune checkpoint is a PD-L1 inhibitor, for example, an anti-PD-L1 monoclonal antibody. In some respects, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG 7446) or MSBO010718C, or any combination thereof. In some ways, the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736. In other respects, the immune checkpoint inhibitor is a CTLA-A4 inhibitor, for example, and anti-CTLA-4 antibody. In some ways, the anti-CTLA-4 antibody is ipilimumab.
[0249] [0249] In other methods in which the disease to be treated is cancer or other proliferative disease, the compounds of the disclosure, as well as the pharmaceutical compositions that comprise them, can be administered in combination with an alkylating agent (for example, cyclophosphamide (CY ), melphalan (MEL)) and bendamustine), a proteasome inhibiting agent (eg carfilzomib), a corticosteroid agent (eg dexamethasone (DEX)) or an immunomodulatory agent (eg lenalidomide (LEN) or pomalidomide ( PO M)) or any combination thereof.
[0250] [0250] In some modalities, the disease to be treated is an autoimmune or inflammatory condition. In these respects, the compounds of the disclosure, as well as the pharmaceutical compositions that comprise them, can be administered in combination with a corticosteroid agent, such as,
[0251] [0251] In other methods in which the disease to be treated is an autoimmune or inflammatory condition, the compounds of the disclosure, as well as the pharmaceutical compositions that comprise them, can be administered in combination with an immune suppressing agent, such as, for example, fluocinolone acetonide (RETISERT T “), rimexolone (AL-2178, VEXOL 'Y, ALCO T“) or cyclosporine (RESTASIS Tm) or any combination thereof.
[0252] [0252] In some modalities, the disease to be treated is beta-thalassemia or sickle cell disease. In these respects, the compounds of the disclosure, as well as the pharmaceutical compositions that comprise them, can be administered in combination with one or more agents, such as, for example, HYDRE AY (hydroxyurea).
[0253] [0253] The examples and preparations provided below illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It should be understood that the scope of the present invention is in no way limited by the scope of the following examples and preparations. In the following examples, molecules with a single chiral center, unless otherwise stated, exist as a racemic mixture. Molecules with two or more chiral centers, unless otherwise indicated, exist as a racemic mixture of diastereomers. And single nantiomers / diasterosisomers can be obtained by methods known to those skilled in the art.
[0254] [0254] The compounds of the disclosure can be prepared, for example, by reference to the following schemes.
[0255] [0255] In some respects, the disclosure compounds include synthetic intermediates useful in the preparation of other disclosure compounds. In this regard, the compounds of the disclosure include, for example, compounds of the formula S1-1, formula S1-2, formula S1-3 and formula S1-4:
[0256] [0256] In some embodiments of the compounds of formula S1-1, S1- 2, SI-3 and SI-4, the aryl is -4-chlorophenyl, 4-chloro-2- (hydroxymethyl) phenyl, -3,4-
[0257] [0257] In some embodiments of the compounds of formula SI-1 and S1- 2, X is chlorine. In other modalities, X is fluorine. In still other modalities, X is bromine.
[0258] [0258] In some embodiments of the compounds of formula S1I-1, S1- 2, SI-3 and SI-4, PG1 and PG2, each is a hydroxyl protecting group or, alternatively, PG1 and PG2, together with the atoms to which they are attached, form a cyclic 1,2-dihydroxyl protecting group.
[0259] [0259] In some embodiments of the compounds of formula S1I-1, S1- 2, SI-3 and SI-4, PG1 and PG2, each is a hydroxyl protecting group. In other embodiments, PG1 and PG2, together with the atom to which they are attached, form a cyclic 1,2-dihydroxyl protecting group. Suitable protecting groups are well known to those skilled in the art. See, for example, Wuts, Peter GM and Theodora W. Greene. Greene's protective groups in organic synthesis. John Wiley & Sons, 2006. In some modalities, PG1 and PG2 together form a ketal. In other embodiments, PG1 and PG2 together form a di-alkyl acetal. In some embodiments, PG1 and PG2 together form an acetonide protecting group, and the compounds have the formula SlI-l1a, SI-2a, Sl-3a and Sl-4a:
[0260] [0260] The specific modalities of compounds of formula S1I-1, S1- 2, Sl-3 and SI-4 are described in the Experimental Procedures section set out below.
[0261] [0261] The compounds of the disclosure include, for example, the compounds identified in Table A. TABLE A
[0262] [0262] To a mixture of Int-1 - 1 compound (40.00 g, 210.31 mmol, 1 eq.) Was added in DCM (400 mL) dropwise TEA (63.84 g, 630.94 mmol, 87.82 mL, 3 eq.), at 0 ° C under N2. BzCl (32.52 g, 231.34 mmol, 26.88 mL, 1.1 eq.) Was added dropwise to the mixture at 0 ° C under N, The mixture was stirred at 0 ° C for 1 h under N7 The mixture was combined with another reaction mixture with 10 g of Int-1-1. The combined mixture was finished with water (600 ml). The organic layer was separated. The aqueous layer was extracted with DCM (300 ml x 3). The combined organic layers were washed with saturated NaHCO3 solution (400 ml), dried over NazS O, filtered and concentrated. The residue was purified by column chromatography (SiO ,, petroleum ether / ethyl acetate = 50/1 to 2/1) to obtain compound 2 (67.00 g, 227.66 mmol, 86.60% yield , 93.43% purity by LCMS) as a yellow solid. '"H NMR (400 MHz, CHLOROPHORMUM-d) 5 = 8.12-7.95 (m, 2H), 7.66-7.53 (m, 1H), 7.51-7.41 (m, 2H), 5.97 (d, / = 3.7 Hz, 1H), 4.87 - 4.75 (m, 1H), 4.60 (d, / = 3.5 Hz, 1H), 4, 47 - 4.35 (m, 2H), 4.19 (dd, / = 2.2, 4.0 Hz, 1H), 3.27 (d, / = 4.0 Hz, 1H), 1.52 (s, 3H), 1.33 (s, 3H).
[0263] [0263] Two batches in parallel: To a mixture of the compound Int-1-2 (10.00 g, 33.98 mmol, 1 eq.) In DCM (100 mL) was added DMP (43.24 9, 101, 94 mmol, 31.56 mL, 3 eq.) At 0 ° C. The mixture was stirred at 15 ° C for 4h. The mixture was filtered and the filtrate was concentrated. The residue was diluted with EtoAc (500 ml) and the mixture was filtered. The filtrate was diluted with saturated NaHCO3; (300 mL). The mixture was extracted with EtoOAc (200 ml * 3). The combined organic layers were washed with brine (300 ml), dried over NazSO4, filtered and concentrated. The residue was purified by column chromatography (SiO ,, petroleum ether / ethyl acetate = 20/1 to 3/1) to obtain Int-1 compound (17.00 9, 58.16 mmol, yield 85, 59% purity) as a white solid. * "H NMR (400 MHz, CHLOROPHORMUM-d) 5 = 8.00-7.91 (m, 2H), 7.65-7.53 (m, 1H), 7.50-7.40 (m, 2H), 6.15 (d, / = 4.4 Hz, 1H), 4.78 - 4.67 (m, 2H), 4.54 - 4.41 (m, 2H), 1.53 (s , 3H), 1.44 (s, 3H) Synthesis of 2-chloroquinoline-7-ol (Int-2)
[0264] [0264] To a mixture of quinoline-2,7-diol (Int-2-1, 5.00 g, 31.03 mmol, 1 eq.) In DMF (50 mL), thionyl chloride ( 14.76 9, 124.10 mmol, 9.00 mL, 4 eq.) At 0 ° C. The mixture was stirred at 20 ° C for 30 min and then stirred at 70 ° C for 2 h. The mixture was concentrated to a residue. The residue was diluted with saturated NaHCO3 (100 mL). The mixture was extracted with EtoOAc (30 mlx4). The combined organic layers were washed with brine (40 ml), dried over NazSO4, filtered and concentrated. The residue was purified by column chromatography (SiO ,, petroleum ether / ethyl acetate = 50/1 to 3/1) to obtain Int-2 compound (5.30 9, 29.51 mmol, yield 95, 11%) as a yellow solid. * H NMR (400 MHz, CHLOROPHORMUM-d) 5 = 8.03 (d, / = 8.4 Hz, 1H), 7.73 (d, / = 8.8 Hz, 1H), 7.34 (d , / = 2.3 Hz, 1H), 7.25 (s, 1H), 7.20 (dd, / = 2.5, 8.9 Hz, 1H), 5.45 (s, 1H).
[0265] [0265] To a mixture of Int-3-1 compound (200 mg, 1.62 mmol, 1 eq.) In THF (6 mL) was added Boc2O (425.32 mg, 1.95 mmol, 447.71 ul) , 1.2 eq.) At 25ºC. The mixture was stirred at 25 ° C for 3 h. LCMS showed that the compound Int-3-1 was consumed and the desired MS was observed. The reaction was terminated by saturated NaHCO3 solution (10 ml), extracted with EtOAc (5 ml x 3). The combined organic layers were dried over Na7zSO4, filtered and concentrated. The residue was purified by column chromatography (SiO>, petroleum ether / ethyl acetate = 1/0 to 1/1) to obtain Int-3 compound (180 mg,
[0266] [0266] A mixture of the compound Int-4-1 (14.59, 94.42 mmol, 1 eq.) And S electfluor (50.17 g, 141.63 mmol, 1.5 eq.) ACN was added (725 mL), ACOH (152.25 g, 2.54 mol, 145 mL, 26.85 eq.) And degassed and purged with N for 3 times, and then the mixture was stirred at 70 ° C for 16 hours under N2 atmosphere LCMS showed that no Int-4-1 compounds were maintained. Several new peaks were shown in the LCMS and - 45% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with toluene (200 ml) and concentrated under reduced pressure to remove the solvent twice. The residue was purified by column chromatography (SiO>, petroleum ether / ethyl acetate = 30/1 to 8/1) to obtain Int-4 compound (10 9, 54.46 mmol, yield of 57.68% , 93.43% purity by LCMS) as a yellow solid. * H NMR (400 MHz, DMSO-ds) 5 ppm 12.49 (br s, 1 H) 8.55-8.67 (m, 1 H) 7.71 (t / = 2.63 Hz, 1 H ); LCMS: (M + H ”): 171.9. Synthesis of Int-5 RR AR THCI, TEA ENS Dad ENS Cc DONO Mao 1 Ag mo 55 end Ao Int-5-1 Int-5-2 Int-5-3 Int-s
[0267] [0267] For a solution of Int-5-1 compound (6 9, 24.74 mmol, 1 eq.) In NH3ºH2O (80 ml) and dioxane (80 ml) was stirred at 120 ° C for 6 hours (50 psi). TLC showed that the compound Int-1-1 was maintained and a new spot was formed. The reaction was cleaned according to TLC (petroleum ether / ethyl acetate = 5: 1, Rf = 0.08). The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H2 O (100 ml) and extracted with EtoOAc (50 ml x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ,, petroleum ether / ethyl acetate = 50: 1 to 1: 1). The Int-5-2 compound (3.25 g, 14.29 mmol, 57.77% yield, 98.11% purity) was obtained as a yellow solid. LCMS: (M + H *): 223.0; TLC (petroleum ether: ethyl acetate = 5: 1) R; = 0.08.
[0268] [0268] To a solution of the compound Int-5-2 (0.29, 896.58 umol, 1 eq.) In ACN (10 mL) was added TEA (181.45 mg, 1.79 mmol, 249, 59 ul, 2 eq.) And TrtC1 (299.93 mg, 1.08 mmol, 1.2 eq.) At 25 ° C. The mixture was stirred at 80 for 0.5 h. TLC showed that Compound Int-5-2 was maintained and a new point was formed (petroleum ether: Ethyl acetate = 3: 1, R; = 0.68). The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H215 ml extracted with DCM (10 ml x 3). The combined organic layers were washed with brine (20 ml x 2), dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ,, petroleum ether / ethyl acetate = 1: 0 to 5: 1) and based on TLC (petroleum ether: ethyl acetate = 3: 1, Rr = 0, 68). The compound Int-5-3 (2 g, 3.45 mmol, 76.90% yield, 80.22% purity) was obtained as a white solid. TLC (petroleum ether: Ethyl acetate = 3: 1) Rx
[0269] [0269] To a solution of compound Int-5-3 (0.6 g, 1.29 mmol, 1 eq.) In dioxane (3 ml) and H 2 O (3 ml) was added KOH (289.36 mg, 5.16 mmol, 4 eq.), X-PPHOS (95.48 mg, 193.39 umol, 0.15 eq.) and Pd> (dba) 3 (118.06 mg, 128.93 umol, 0.1 eq.) Under N; at 25ºC. The mixture was stirred at 80 ° C for 16 hours. LC-MS showed that no Int-5-3 compounds were maintained. A major peak was shown on LC-MS and the desired compound was detected. The reaction mixture was filtered and the solution was concentrated under reduced pressure to remove the solvent. The residue was diluted with H, 10 ml extracted with DCM (15 ml x 2). The combined organic layers were washed with brine (10 ml x 2), dried over Na 2 SO a, filtered and concentrated under reduced pressure to give a residue. The residue was purified by means of prep-TLC (SiO ,, petroleum ether / ethyl acetate = 1: 1, 5% TEA) and based on TLC (petroleum ether / ethyl acetate = 1: 1, Rs = 0.21, 5% TEA). The Int-5 compound (0.23 9, crude) was obtained as a yellow solid. TLC (petroleum ether: ethyl acetate = 1: 1.5% TEA) R; = 0.21; LCMS: (M + H *): 403.1.
[0270] [0270] To a solution of Mg (979.09 mg, 40.28 mmol, 1.3 eq.) Was added the compound Int-6-1 (7 g, 30.99 mmol, 1 eq.) In THF ( 26 mL) at 40ºC under N>. The mixture was stirred at 40 ° C for 0.5 h. Mg was consumed. The compound
[0271] [0271] To a mixture of Mg (362.73 mg, 14.92 mmol, 1.5 eq.) And |, (252.52 mg, 994.94 umol, 200.42 µL, 0.1 eq.) the compound Int-7-1 (2 9, 9.95 mmol, 1.19 ml, 1 eq.) in THF (20 ml) was added at 25 ° C under N7. The mixture was stirred at 25 for 0.5 h. Mg was consumed. The compound Int-7 (2.24 g, crude) in THF (20 mL) was obtained as a brown oil which was used for the next step.
[0272] [0272] A 50 mL RBF with septum containing Mg (34.01 mg, 1.42 mmol) was dried under high vacuum with a heat gun and cooled under Ar. The flask was charged with THF (0.40 mL) , 2/5 portion of 4-bromo-1-chloro-2-methylbenzene (0.19 mL, 1.34 mmol) and a drop of DIBAL (1M, toluene). The reaction was stirred at room temperature, but no exotherm was observed, which could mean that the magnesium was not starting. Another drop of DIBAL was added and this time there was an exotherm. After stirring for 10 min, the remaining 4-bromo-1-chloro-2-methylbenzene and another THF (0.30 mL) were added and stirring was continued for 1 h. As all the magnesium dissolved, the Grignard Int-8 reagent was used as it was.
[0273] [0273] To a solution of 3-bromo-2-chloro-7-methoxy-quinoline (Int-9-1, WO2017 / 032840 Al) (640 mg, 2.35 mmol) in chloroform (70 mL) was added tribromide boron (4.4 mL, 46.97 mmol) at 0 ° C, the reaction mixture was stirred at 80 ° C overnight. TLC (PE: EA = 1: 1, DEF = 0.5) and LCMS showed 12% of remaining SM. The reaction was finished with MeOH, slowly at 0ºC, EA was added and adjusted to pH 8 with aqueous NaHCO; 3. The organic phase was separated and washed with brine. The organic phase was concentrated in vacuo to give the crude product which was purified by column chromatography on silica gel (PE: EA = 2: 1a PE: EA = 1: 1) to give 3-bromo-2-chloro-quinolin- 7 -ol (Int-9) (339 mg, 1.28552 mmol, 54.727% yield) as a white solid. LCMS M + H *: 258 / 260.1 / 262 Example 1. (2R, 3S, 4R, 5R) -5- (4-amino-7H-pyrrolo [2,3-d] pyrimidin-7-i1) - 2 - ((((2-aminoquinolin-7-yl) oxy) methyl) -3-methyltetrahydrofuran-3,4-diol (1) BO OO HO OOo ne / (y O OOo Inta MEMES A NeoMe NO O PRI BEAR CO E OX THF mol o MeoH mol THF a ”noy 1a 1a 1b 1e" OA A a. Ter (QT meet (2nd Cl HO cl HO 1d 1e ms PN NH And EDS HoN Ho Ex. 1
[0274] [0274] To a mixture of Int-1 (17.00 g, 58.16 mmol, 1 eq.) In THF (200 mL) was added dropwise MeMgBr (3 M, 58.16 mL, 3 eq.) at -78ºC under N2. The mixture was stirred at -78 ° C for 1 h under N2. The combined mixture was quenched by means saturated with NHa 4 Cl (200 ml), extracted with EtOAc (50 ml * 3). The combined organic layers were washed with brine (100 ml), dried over NazSOa, filtered and concentrated. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 15/1 to 5/1) for compound 1a as a white solid. * H NMR (400 MHz, CHLOROPHORMUM-d) 5 = 8.13-8.01 (m, 2H), 7.64-7.51 (m, 1H), 7.48-7.38 (m, 2H ), 5.83 (d, / = 4.0 Hz, 1H), 4.57 (dd, / = 3.1, 11.9 Hz, 1H), 4.38 (dd, / = 8.2, 11.9 Hz, 1H), 4.21 - 4.06 (m, 2H), 2.71 (s, 1H), 1.60 (s, 3H), 1.37 (s, 3H), 1, 26 (s, 3H).
[0275] [0275] A mixture of compound 1a (2.309, 7.46 mmol, leg.) And MeONa (806.00mg, 14.92 mmol, 2eq.) In MeOH (20 mL) was stirred at 15 ° C for 0.5 h. The mixture was quenched by solid NH4 Cl (4 g) and filtered. The filtrate was concentrated. The crude product was purified by column chromatography (SiO>, petroleum ether / ethyl acetate = 5/1 to 1/1) to obtain compound 1b (1.30 9, 6.37 mmol, yield 85.34 %) as a yellow solid. * H NMR (400 MHz, CHLOROPHORUM-d) 5 = 5.80 (d, / = 4.0 Hz, 1H), 4.13 (d, / = 3.7 Hz, 1H), 3.96-3 , 71 (m, 3H), 2.67 (s, 1H), 1.81 - 1.69 (m, 1H), 1.60 (s, 3H), 1.37 (s, 3H), 1, 18 (s, 3H) Step 3. Preparation of (3aR, 5R, 6R, 6aR) -5 - ((((2-chloroquinolin-7-yl) oxy) methyl) -2,2,6-trimethyltiltetrahydrofuro [2,3 -d] [1,3] dioxol -6-o01 (1c)
[0276] [0276] To a mixture of PPh3 (3.50 g, 13.35 mmol, 3 eq.) And DEAD (1.55 g, 8.90 mmol, 1.62 mL, 2 eq.) In THF (15 mL ) was stirred at 20 ° C for 30 min under N. 2-Chloroquinoline-7-ol (Int-2, 799.51 mg, 4.45 mmol, 1 eq.) Was added to the mixture followed by compound 1b (1.00 g, 4.90 mmol, 1.1 eq. .) at 20ºC. The mixture was stirred at 20ºC for 12 h. The mixture was finished with water (20 ml), extracted with EtOAc (10 ml x 2). The combined organic layers were washed with brine (20 ml), dried over Na7SSO4, filtered and concentrated. The residue was purified by column chromatography (SiO ,, petroleum ether / ethyl acetate = 1/0 to 3/1) to obtain compound 1c (1.49, crude) as a white solid. LCMS: (M + H *): 366.1.
[0277] [0277] A mixture of Compound 1c (900 mg, 2.46 mmol, 1 eq.) In TFA (10 ml) and HO (1 ml) was stirred at 20 ° C for 0.5 h. The mixture was concentrated and the residue was dissolved in EtO Ac (15 ml). Saturated NaHCO3 solution (30 ml) was added to the solution and the organic layer was separated. The mixture was extracted with EtOAc (15 ml x 4). The combined organic layers were dried over Na7SO4; filtered and concentrated. The residue was purified by column chromatography (SiO ,, petroleum ether / ethyl acetate = 3/1 to 1/0) to obtain compound 1d (280 mg, 845.67 umol, 34.37% yield) as a white solid. * H NMR (400 MHz, METANOL-da) 5 = 8.26 (d, / = 8.6 Hz, 1H), 7.88 (d, J = 9.3 Hz, 1H), 7.45 - 7 , 25 (m, 3H), 5.39 - 5.20 (m, 1H), 4.59 (s, 1H), 4.40 (dd, J = 3.4, 5.6 Hz, 1H), 4.35 - 4.07 (m, 3H), 3.86 (d, / = 4.4 Hz, 1H), 3.68 (d, / = 3.5 Hz, 1H), 1.37 (d , / = 17.5 Hz, 3H).
[0278] [0278] To a mixture of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (127.29 mg, 828.87 umol, 1 eq.) In THF (10 ml) was added pyridine (65.56 mg, 828.87 umol, 66.90 ul, 1 eq.) at 25 ° C. DIAD (335.21 mg, 1.66 mmol, 322.32UL, 2 Step 6) was prepared. Preparation of (2R, 3S5.4R, 5R) -5- (4-amino-7H-pyrrolo [2,3- dlpirimidin-7-i1) -2 - ((((2-aminoquinolin-7-yl) oxy) Methyl) -3-methyltetrahydrofuran-3,4-diol (1)
[0279] [0279] A mixture of compound le (80 mg, 173.42 umol, 1 eq.) And NH3-H2O (36.40 g, 259.66 mmol, 40.00 ml, 1497.27 eq.) In dioxane ( 2 mL) was stirred at 145 ° C for 48 h. The mixture was concentrated. The residue was purified by prep-HPLC ([water (10 MM NHaHCO; 3) -ACN] J; B%: 20% -50%) to give compound 1 (9.13 mg, 21.33 umol, yield 12.30%, 98.71% purity) as a light yellow solid. * H NMR (400 MHz, DMSO-d 6) 5 = 8.07 (s, 1H), 7.80 (d, | = 8.8 Hz, 1H), 7.55 (d, | = 8.8 Hz, 1H), 7.41 (d, | = 3.7 Hz, 1H), 7.04 - 6.92 (m, 3H), 6.87 (dd, / = 2.4, 8.7 Hz , 1H), 6.64 - 6.57 (m, 2H), 6.33 (s, 2H), 6.17 (d, J = 7.9 Hz, 1H), 5.37 (d, / = 7.2 Hz, 1H), 5.00 (s, 1H), 4.42 (t / = 7.5 Hz, 1H), 4.27 - 4.13 (m, 3H), 1.30 (s 3H); 1 H NMR (400 MHz, DMSO-d6 + D20) δ5 = 8.07 (s, 1H), 7.81 (d, | = 8.8 Hz, 1H), 7.56 (d, | = 8, 7 Hz, 1H), 7.40 (d, | = 3.8 Hz, 1H), 6.99 - 6.84 (m, 2H), 6.67 - 6.57 (m, 2H), 6, 17 (d, | = 7.9 Hz, 1H), 4.42 (d, | = 7.9 Hz, 1H), 4.24 - 4.12 (m, 3H), 1.30 (s, 3H ) LCMS: (M + H +): 423.1.
[0280] [0280] A mixture of Int-1 compound (4.00 g, 13.69 mmol, 1 eq.) In THF (40 mL) was degassed and purged with N2 for 3 times, and then the mixture was cooled at 0ºC, and then TMSCF3 was added to the mixture (4.09 g, 28.74 mmol, 2.1 eq.), TBAF (1 M, 13.69 ml, 1 eq.), then the mixture was stirred at 0ºC for 1 h under N atmosphere, TLC indicated that the Int-1 compound was completely consumed and new points formed. The reaction was cleaned up according to TLC. The reaction was terminated by sat. ag. NHACI (10 ml), and extracted with EtOAc (10 ml x 2), and then the organic phase was concentrated in vacuo. Compound 2a (4 g, crude) was obtained as a yellow oil. TLC (petroleum ether: Ethyl acetate = 3: 1) R; = 0.29.
[0281] [0281] To a solution of compound 2a (4.00 g, 11.04 mmol, 1 eq.) In MeOH (20 mL) was added NaOMe (1.19 g, 22.08 mmol, 2 eq.). The mixture was stirred at 25 for 0.5 h. TLC indicated that compound 2a was consumed completely and new spots were formed. The reaction was cleaned up according to TLC. The reaction was terminated by means of NH.CI (209), and filtered, the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO ,, petroleum ether / ethyl acetate = 4/1 to 1: 0). Compound 2b (2.6 g, crude) was obtained as a white solid. TLC (petroleum ether: Ethyl acetate = 3: 1) Rr = 0.07.
[0282] [0282] A mixture of PPh3 (5.28 9, 20.14 mmol, 2 eq.) In THF (20 mL) was degassed and purged with N> for 3 times, and then the mixture was cooled to 0 ° C. , then the mixture was added DEAD (3.519, 20.14 mmol, 3.66 mL, 2 eq.) stirred at 0 ° C for 30 min, then compound 2b (2.6 9, 10.07 mmol, 1 eq. .) and 2-chloroquinolin-7-ol (2.17 g, 12.08 mmol, 1.2 eq.) was added at 0 ° C, the mixture was stirred at 25 ° C for 12 h under a N atmosphere. LC-MS showed that compound 2b was completely consumed and a major peak with the desired mass was detected. TLC indicated that compound 2b was completely consumed and new spots formed. The reaction was cleaned up according to TLC. The mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO ,, petroleum ether / ethyl acetate = 4/1 to 1: 1). Compound 2c (1.5 g, crude) was obtained as a yellow oil. LCMS: (M + H *): 420.0; TLC (petroleum ether: Ethyl acetate = 3: 1) R; = 0.36.
[0283] [0283] To compound 2c (1.50 g, 3.57 mmol, 1 eq.) Was added TFA (452.71 mg, 3.57 mmol, 293.97 ul, 90% purity, 1 eq.), the mixture was stirred at 25 ° C for 20 min. TLC indicated that compound 2c was completely consumed and new spots were formed. The reaction was cleaned up according to TLC. The reaction was quenched by NaHCO; 3 sat. (30 ml) and then extracted with EtO Ac (10 ml x 2). The combined organic layer was washed with brine (10 ml), dried over Na> 2S O, filtered and concentrated. The crude product compound 2d (1 g, crude) was used in the next step without further purification as a yellow oil. TLC (petroleum ether: Ethyl acetate = 1: 1) R; = 0.24.
[0284] [0284] A solution of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (161.77 mg, 1.05 mmol, 1 eq.) In THF (10 mL) was added pyridine (83.33 mg , 1.05 mmol, 85.03 ul, 1 eq), DIAD (426.02 mg, 2.11 mmol, 409.64 ul, 2 eq.), Tributylphosphane (426.26 mg, 2.11 mmol, 519 , 83 ul, 2 eq.), Compound 2d (400 mg, 1.05 mmol, 1 eq.), All at once, the mixture was stirred at 25 ° C for 12 h under N> LC-MS showed that the compound 2d was completely consumed and a main peak with the desired mass was detected. The mixture was concentrated in vacuo. The residue was dissolved in H2O (10 ml), and then extracted with EtO Ac (10 ml x 3), the organic phase was concentrated in vacuo. The residue was purified by column chromatography (SiO ,, petroleum ether / ethyl acetate = 10/1 to 4: 1). Compound 2e (300 mg, crude) was obtained as a white solid. TLC (petroleum ether: Ethyl acetate = 1: 1) R; = 0.58.
[0285] [0285] To a solution of compound 2e (300 mg, 582.22 umol, 1 eq.) In dioxane (3 ml) was added NH3ºH2O (19.98 g, 142.50 mmol, 21.95 ml, 25% purity, 244.75 eq.), the mixture was stirred at 145ºC for 12 h. LC-MS showed that compound 2e was completely consumed and a major peak with the desired MS was detected. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (basic condition, HPLC: column: Águas Xbridge Prep OBD C18 150 * 30 10 u; in the mobile phase: [water (0.04% NH3H20) - ACNJ; B%: 10% - 40 %, 10 min). Compound 3 (15.73 mg, 32.58 umol, 5.60% yield and 98.67% LCMS purity) was obtained as a white solid. * 'H NMR (400 MHz, DMSO-d 5) 5 = 8.08 (s, 1H), 7.78 (d, / = 8.6 Hz, 1H), 7.52 (d, / = 8, 8 Hz, 1H), 7.44 (d, / = 3.5 Hz, 1H), 7.08 (br s, 2H), 6.86 (d, / = 2.4 Hz, 1H), 6, 82 - 6.76 (m, 2H), 6.65 (d, / = 3.5 Hz, 1H), 6.59 (d, / = 8.8 Hz, 1H), 6.35 (s, 2H ), 6.21 (d, / = 7.3 Hz, 1H), 6.15 (d, / = 7.7 Hz, 1H), 4.99 (t / = 7.5 Hz, 1H), 4 , 41 - 4.25 (m, 3H); 'H NMR (400 MHz, DMSO-d; + D 7 0) 5 = 8.05 (s, 1H), 7.77 (d, / = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.41 (d, / = 3.5 Hz, 1H), 6.84 (d, / = 2.2 Hz, 1H), 6.78 (dd, / = 2 , 5, 8.7 Hz, 1H), 6.63 (d, / = 3.7 Hz, 1H), 6.58 (d, / = 8.8 Hz, 1H), 6.12 (d, / = 7.9 Hz, 1H), 4.97 (d, / = 7.7 Hz, 1H), 4.39 - 4.22 (m, 3H); LCMS: (M + H *): 477.1; HPLC purity: 100.0%.
[0286] [0286] A mixture of Int-1 compound (4.00 g, 13.69 mmol, 1 eq.) In THF (40 mL) was degassed and purged with N2 for 3 times, and then the mixture was cooled at 0 ° C, and then to the mixture was added bromine (ethinyl) magnesium (0.5 M, 41.06 ml, 1.5 eq.), then the mixture was stirred at 0 ° C for 3 h under Nx atmosphere. TLC indicated that the Int-1 compound was completely consumed and a new spot was formed. The reaction was cleaned up according to TLC. The reaction was terminated by sat. aq. NHaCI sat. aq. (4 ml) and extracted with EtOAc (5 ml x 3). The organic phase was concentrated in vacuo. Compound 3a (4 g, crude) was obtained as a yellow oil. TLC (petroleum ether: Ethyl acetate = 2: 1) R; = 0.43. Step 2. Preparation of (3aR, 5R, 6R, 6aR) -6-ethinyl-5- (hydroxymethyl) -2,2-dimethyl tetrahydrofuro [2,3-d] [1,3] dioxol-6-o01 (3b )
[0287] [0287] To a solution of compound 3a (4.009, 12.57 mmol, 1 eq.) In MeOH (30 ml) was added NaOMe (1.36 g, 25.13 mmol, 2 eq.). The mixture was stirred at 25 for 0.5 h. TLC indicated that compound 3a was completely consumed and new spots were formed. The reaction was cleaned up according to TLC. The reaction was terminated by means of NHaCI (20 g), and then filtered, and the filtrate was concentrated in vacuo at 25ºC. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 4/1 to 1: 1). Compound 3b (2.6 g, crude) was obtained as a white solid. TLC (petroleum ether: ethyl acetate = 1: 1) R $ = 0.24.
[0288] [0288] A mixture of PPh3 (6.37 9, 24.27 mmol, 2 eq.) In THF (20 mL) was degassed and purged with N> for 3 times, and then the mixture was cooled to 0 ° C. , and then the mixture was added DEAD (4.239, 24.27 mmol, 4.41 mL, 2 eq.), the mixture was stirred at 0 ° C for 30 min, then the mixture was added 2-chloroquinolin-7 -ol (2.62 g, 14.56 mmol, 1.2 eq.), then compound 3b (2.60 g, 12.14 mmol, 1 eq.) was added to the mixture at 0 ° C, then the mixture it was stirred at 25ºC for 12 h under N2 atmosphere. TLC indicated that compound 3b was completely consumed and new spots formed. The reaction was cleaned up according to TLC. The reaction was concentrated in vacuo at 25ºC. The residue was purified by column chromatography (SiO ,, petroleum ether / ethyl acetate = 4/1 to 4: 1). Compound 3c (2.4 g, crude) was obtained as a white solid. TLC (petroleum ether: Ethyl acetate = 3: 1) R; = 0.62.
[0289] [0289] To a solution of compound 3c (2.40 g, 6.39 mmol, 1 eq.) Was added TFA (809.08 mg, 6.39 mmol, 525.38 µl, 90% purity, 1 eq. .), the mixture was stirred at 25ºC for 20 min. TLC indicated that compound 3c was completely consumed and new spots formed. The reaction was cleaned up according to TLC. The reaction was quenched by NaHCO; 3 sat. (30 ml) and then extracted with EtOAc (10 ml x 2). The combined organic layer was washed with brine (10 ml), dried over Na2zSO2., Filtered and concentrated. The crude product compound 3d (1.9 g, crude) was used in the next step without further purification as a yellow oil. TLC (petroleum ether: ethyl acetate = 1: 1) R; = 0.24.
[0290] [0290] A solution of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (182.96 mg, 1.19 mmol, 1 eq.) In THF (10 mL) was added pyridine (94.24 mg , 1.19 mmol, 96.16 ul, 1 eq), DIAD (481.83 mg, 2.38 mmol, 463.29 ul, 2 eq.), Tributylphosphane (482.09 mg, 2.38 mmol, 587 , 91 ul, 2 eq.), Compound 3d (400 mg, 1.19 mmol, 1 eq.), All at once, the mixture was stirred at 25 ° C for 12 h under N> LC-MS showed that the compound 3d was completely consumed and a main peak with the desired DM was detected. The mixture was concentrated in vacuo. The residue was dissolved in H2O0 (10 ml), and then extracted with EtOAc (10 ml * 3), the organic phase was concentrated in vacuo. The residue was purified by column chromatography (SiO ,, petroleum ether / ethyl acetate = 10/1 to 4: 1). Compound 3e (300 mg, crude) was obtained as a white solid. TLC (petroleum ether: Ethyl acetate = 2: 1) R; = 0.12; LCMS: (M + H *): 473.0.
[0291] [0291] To a solution of compound 3e (300 mg, 636.55 umol, 1 eq.) In dioxane (3 ml) was added NH3'H2O (5.46 g, 155.80 mmol, 6 ml, 244.75 eq.). The mixture was stirred at 145ºC for 12 h. LC-MS showed that compound 3e was completely consumed and a major peak with the desired MS was detected. The mixture was concentrated in vacuo. The residue was purified by preparing
[0292] [0292] A mixture of Int-1 compound (3.00 g, 10.26 mmol, 1 eq.) In THF (20 mL) was degassed and purged with N for 3 times, and then the mixture was cooled to -78 ° C, and then to the mixture bromine (vinyl) magnesium (1M, 20.53 mL, 2 eq.) was added, then the mixture was stirred at -78 ° C for 3 h under N2 atmosphere . LC-MS showed that the compound Int-1 was completely consumed and a main peak with the desired mass was detected. The reaction was terminated by sat. ag. NHaCI (10 ml), and then extracted with EtO Ac (10 ml x 3), and then the organic phase was concentrated in vacuo. Without purification. Compound 4a (3.29 g, crude) was obtained as a yellow solid. LCMS: (M + H *): 319.1.
[0293] [0293] To a solution of compound 4a (3.29 g, 10.27 mmol, 1 eq.) In MeOH (30 ml) was added NaOMe (1.11 g, 20.54 mmol, 2 eq.). The mixture was stirred at 25 for 0.5 h. TLC indicated that compound 4a was completely consumed and new spots were formed. The reaction was cleaned up according to TLC. The reaction was terminated by means of NH, CI (209), and filtered, the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO ,, petroleum ether: Ethyl acetate = 5/1 to 1: 1). Compound 4b (1.99, crude) was obtained as a white solid. * HNMR (400 MHz, CHLOROPHORUM-d) 5 = 5.85 (d, J = 3.7 Hz, 1H), 5.81 - 5.71 (m, 1H), 5.53 (dd, / = 1 , 2, 17.2 Hz, 1H), 5.30 (dd, / = 1.1, 11.0 Hz, 1H), 4.23 (d, / = 3.8 Hz, 1H), 4.00 (t / = 5.6 Hz, 1H), 3.69 (d / = 5.7 Hz, 2H), 1.61 (s, 3H), 1.37 (s, 2H), 1.40 - 1 , 33 (m, 1H).
[0294] [0294] A mixture of PPh3 (4.65 9, 17.74 mmol, 2 eq.) In THF (20 mL) was degassed and purged with N> for 3 times, and then the mixture was cooled to 0 ° C. , and then the mixture was added DEAD (3.09 9, 17.74 mmol, 3.22 mL, 2 eq.), the mixture was stirred at 0 ° C for 30 min, then the mixture was added 2- chloroquinolin-7-ol (1.91 g, 10.64 mmol, 1.2 eq.), then compound 4b (1.92 g, 8.87 mmol, 1 eq.) was added to the mixture at 0 ° C, then the mixture was stirred at 25ºC for 12 h under N2 atmosphere. LC-MS showed that compound 4b was completely consumed and a major peak with the desired MS was detected. The reaction was concentrated in vacuo at 25ºC. The residue was purified by column chromatography (SiO>, petroleum ether / ethyl acetate = 4/1 to 4: 1). Compound 4c (1.2 g, crude) was obtained as a white solid. * H NMR (400 MHz, CHLOROPHORMUM-d) 5 = 8.01 (d, / = 8.6 Hz, 1H), 7.73-7.64 (m, 1H), 7.33 (d, / = 2.4 Hz, 1H), 7.27 (d, / = 2.6 Hz, 1H), 7.26 - 7.23 (m, 1H), 5.95 (d, J = 3.7 Hz, 1H), 5.87 - 5.76 (m, 1H), 5.70 - 5.58 (m, 1H), 5.38 (dd, / = 1.4, 10.9 Hz, 1H), 4 , 36 - 4.31 (m, 1H), 4.29 (d, / = 4.0 Hz, 1H), 4.17 (dd, / = 1.9, 10.7 Hz, 1H), 4, 10 - 4.06 (m, 1H), 1.66 (s, 3H), 1.40 (s, 3H); LCMS: (M + H *): 378.1.
[0295] [0295] A compound of 4c € solution of (400 mg, 1.06 mmol, 1 eq.) In TFA (120.72 mg, 1.06 mmol, 78.39 ul, 1 eq.), The mixture was stirred at 25ºC for 1 h. LC-MS showed that the 4 € compound was completely consumed and a main peak with the desired mass was detected. The mixture was concentrated in vacuo, then dissolved in toluene (10 ml), and then concentrated in vacuo, and repeated this three times. The crude product compound 4d (400 mg, crude, TFA) was as a yellow oil and used in the next step without further purification. LCMS: (M + H *): 338.2.
[0296] [0296] A solution of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (136.40 mg, 888.22, 1 eq.) In THF (10 mL) was added pyridine (70.26 mg, 888.22, 71.69 ul, 1 eq.), DIAD (359.21 mg, 1.78 mmol, 345.39 uL, 2 eq.), Tributylphosphane (359.40 mg, 1.78 mmol, 438, 30 ul, 2 eq.), Compound 4d (300 mg, 888.22, 1 eq.), All at once, the mixture was stirred at 25 ° C for 12 h under No LC-MS showed that compound 4d was completely consumed and a main peak with the desired DM was detected. The mixture was concentrated in vacuo. The residue was dissolved in HO (10 ml), and then extracted with EtOAc (10 ml x 3), the organic phase was concentrated in vacuo. The residue was purified by means of prep-TLC (SiO ,, petroleum ether: ethyl acetate = 3: 1). Compound 4e (400 mg, crude) was obtained as a yellow oil. TLC (petroleum ether: ethyl acetate = 3: 1) Rr = 0.37; LCMS: (M + H *): 473.0.
[0297] [0297] To a solution of 4 € e compound (20 mg, 42.26 umol, 1 eq.) In dioxane (3 ml) was added NH3.H2O (5.46 g, 38.95 mmol, 6 ml, 25 %, 921.74 eq.). The mixture was stirred at 145ºC for 12 h. LC-MS showed that compound 4e was completely consumed and a major peak with the desired MS was detected. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (basic condition; column: YMC-Actus Triart C18 100 * 30 mm * 5 um; in the mobile phase: [water (10 MM NHaHCO; 3) - ACNJ; B%: 15% - 35 %, 12 min). Compound 4 was obtained in batch 1 (2.7 mg, 98.93%) and in batch 2 (9.29 mg, 95%) as a white solid. (Lot 1) * H NMR (400 MHz, DMSO-d 6) 5 = 8.07 (s, 1H), 7.80 (brd, / = 8.7
[0298] [0298] To a mixture of the compound Int-4 (94.80 mg, 552.58 umol, 1.2 eq.) In THF (4 ml) was added pyridine (36.42 mg, 460.48 umol, 37, 17 ul, 1 eq.) At 25 ° C. DIAD (186.23 mg, 920.97 pmol, 179.07 µL, 2 eq.) Was added followed by tributylphosphane (186.33 mg, 920.97 pmol, 227.23uL, 2 eq.) At 25 ° C under N2. Compound 1d (150.00 mg, 460.48 umol, 1 eq.) Was added at 25 ° C under N,>. The mixture was stirred at 25 ° C for 12 h under N2. LCMS showed that compound 1d was consumed and the desired MS was observed. The mixture was concentrated. The residue was dissolved in EtO Ac (50 ml). Water (20 ml) was added to the mixture. The organic layer was separated. The mixture was extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine (20 ml), dried over Naz2SOa, filtered and concentrated. The residue was purified by means of prep-TLC (SiO ,, petroleum ether / ethyl acetate = 1/3) to give Compound 6A (100 mg, 140.99 umol, 30.62% yield, purity 67, 6% by LCMS) as a yellow solid. LCMS: (M + H *): 479.0.
[0299] [0299] A mixture of compound 6a (50 mg, 104.32 umol, 1 eq.) And NH3ºH7O (3.64 9, 25.97 mmol, 4 ml, 248.91 eq.) In dioxane (3 ml) stirred at 145 ° C for 24 h. LCMS showed that compound 6a was consumed. The mixture was concentrated. The residue was purified by prep-HPLC (column: UniSil 120 * 30 * 10 um; in the mobile phase: [water (0.05% HCl) - ACNJ; B%: 1% - 20%, 11 min). Compound 6 (7.24 mg, 15.27 umol, 14.64% yield, 92.88% purity by LCMS) was obtained as a brown solid. * H NMR (400 MHz, DMSO-d6) 5 = 13.95 (broad s, 1H), 8.49-8.17 (m, 4H), 7.89 (d, / = 8.9 Hz, 1H ), 7.60 (s,
[0300] [0300] To a solution of compound 19a (150 mg, 441.47 umol, 1 eq.) In H, O (0.3 ml) and dioxane (30 ml) was added Cs.CO; 3 (431.52 mg , 1.32 mmol, 3 eq.) And 2, 4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (2.69 g, 10.73 mmol, 3.00 mL, 24, 31 eq.) And Pd (dppf) CI> (32.30 mg, 44.15 mmol, 0.1 eq.) In N>. The mixture was stirred at 80 ° C for 16 h under N2 LC-MS showed that no compound 19a was maintained. Several new peaks were shown on LC-MS and - 58% of the desired compound 10a was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water 30 ml and extracted with DCM (30 ml x 3). The combined organic layers were washed with brine (30 ml x 2), dried over Na7SO4Oa, filtered and concentrated under reduced pressure to give a residue. The residue was purified by means of prep-TLC (SiO ,, petroleum ether / ethyl acetate = 0: 1). Compound 10a (70 mg, 219.19 umol, 49.65% yield) was obtained as a yellow oil. * H NMR (400 MHz, CHLOROFORM-d) 5 = 8.69 (s, 1 H), 7.21 - 7.15 (m, 3 H), 7.13 - 7.06 (m, 1 H) , 6.52 (d, / = 3.7 Hz, 1 H), 6.13 (d, / = 3.4 Hz, 1 H), 4.78 (d, / = 3.4 Hz, 1 H ), 4.21 (dd, / = 3.4, 4.8 Hz, 1 H), 3.92 - 3.81 (m, 1 H), 3.79 - 3.69 (m, 1 H) , 3.47 (brs, 1 H), 2.66 (s, 3 H), 2.28 (s, 1 H), 1.64 (s, 3 H), 1.57 (s, 3H), 1.38 (s, 3H); TLC (SiO ,, petroleum ether / ethyl acetate = 0: 1): Rs = 0.45; LCMS: (M + H *): 320.1.
[0301] [0301] To a mixture of compound 10a (120 mg, 375.76 umol, 1 eq.) And Int-5 compound (196.61 mg, 488.48 umol, 1.3 eq.) In toluene (3 ml ) 2- (tributyl-phosphanylidene) acetonitrile (181.38 mg, 751.52 umol, 2 eq.) was added in one portion at 25ºC under N7. The mixture was stirred at 80 ° C for 12 h. LC-MS showed that no compound 10a was maintained. Several new peaks were shown on LC-MS and 55% of the desired compound 10b was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 10 ml water and extracted with 20 ml EtOAc (10 ml x 2). The combined organic layers were washed with 10 ml brine, dried over Naz2CO2, filtered and concentrated under reduced pressure to give a residue. The residue was purified by means of prep-TLC (SiO>, petroleum ether / ethyl acetate = 5: 1). Compound 10b (100 mg, 133.56 umol, 35.54% yield, 94% purity) was obtained as a yellow solid. * H NMR (400 MHz, CHLOROPHORM-d) õ = 8.80 (s, 1 H), 7.39-7.34 (m, 7 H), 7.30-7.22 (m, 10 H) , 6.98 (s, 1 H), 6.84 (dd,)
[0302] [0302] To a solution of compound 10b (0.1 g, 142.08 umol, 1 eq.) Was added TFA (1.54 g, 12.16 mmol, 1 ml, 90% purity, 85.55 eq. .). The mixture was stirred at 25 ° C for 5 min. LC-MS showed that no compound 10b remained. Several new peaks were shown on LC-MS and the desired compound 10 was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was added to NH3-H2O at a pH adjusted to about 8. The residue was purified by prep-HPLC (basic condition: column: Águas Xbridge 150 * 25 5u; in the mobile phase: [water (0.04% NH3ºH27O +10 mM NHaHCO; 3) - ACNJ; B%: 5% -35%, 10 min). Compound 10 (27.28 mg, 64.54 umol, 45.42% yield, 99.70% purity) was obtained as a white solid. * 'H NMR (400 MHz, DMSO-d6) 5 = 8.66 (s, 1 H), 7.80 (dd, J = 2.4, 6.4 Hz, 2H), 7.55 (d, |) = 8.8 Hz, 1 H), 6.95 (d, |) = 2.2 Hz, 1 H), 6.87 (dd, | = 2.6, 8.8 Hz, 1 H) , 6.78 (d, | = 3.9 Hz, 1 H), 6.59 (d, | = 9.2 Hz, 1 H), 6.33 (s, 2 H), 6.30 (d , | = 8.3 Hz, 1 H), 5.46 (brd, | = 6.6 Hz, 1 H), 5.11 (s, 1 H), 4.48 (t |) = 7.0 Hz, 1 H), 4.27 - 4.16 (m, 2 H), 2.64 (s, 3 H), 1.31 (s, 3 H); * H NMR (400 MHz, DMSO-d6 + D20) õ = 8.64 (s, 1 H), 7.82 (d, | = 8.8 Hz, 1 H), 7.75 (d, | = 3.5 Hz, 1 H), 7.57 (d, | = 8.8 Hz, 1 H), 6.96 - 6.86 (m, 2 H), 6.77 (d, | = 3, 9 Hz, 1 H), 6.61 (d, | = 8.8 Hz, 1 H), 6.28 (d, | = 7.9 Hz, 1 H), 4.47 (d, | = 7 , 9 Hz, 1 H), 4.24 - 4.17 (m, 3 H), 2.63 (s, 3
[0303] [0303] For a solution of [(3aR, 4R, 6R, 6aR) -6- (4-chloropyrrolo [2,3-d] pyrimidin-7-yl) -2,2,3a-trimethyl-6, 6a- dihydro-4H-hole [3,4-d] [1,3] dioxol-4-yl] methanol (19a) (137.5 mg, 0.40 mmol) and 3-bromo-2-chloro-quinolin -7-ol (Int-9) (95.0 mg, 0.37 mmol) in toluene (5.0 mL), cyanomethylenetributylphosphorane (0.14 mL, 0.55 mmol) was added at room temperature. The mixture was stirred at 100 ° C for 18 h under N7. The mixture was diluted with DCM (50.0 ml) and washed with brine (20.0 ml x 3), dried over Naz2S Ou, filtered and concentrated in vacuo to give crude product which was purified by silica gel column chromatography (EA: PE = 2: 1) to obtain 7 - [[[3aR, 4R, 6R, 6aR) -6- (4-chloropyrrolo [2,3-d ]
[0304] [0304] A solution of 7 - [[[3aR, 4R, 6R, 6aR) -6- (4-chloropyrrolo [2,3-d] pyrimidin-7-yl) -2,2,3a-trimethyl-6, 6a-dihydro -4H-hole [3,4-d] [1,3] dioxol-4-yl] methoxy] -3-bromo-2-chloro-quinoline (12a) (38.0 mg, 0.07 mmol ) in 1,4-dioxane (1.0 mL) and ammonium hydroxide (1.5 mL, 39.69 mmol) was stirred at 140ºC for 68 h in an autoclave. LCMS showed that the reaction was carried out and 16.0% of SM was left. The mixture was concentrated in vacuo to give the crude product 12b (37.0 mg) which was used directly in the next step. LCMS [M + H] J: 541.1 Step 3. Preparation of (2R, 3S, 4R, 5R) -2 - ((((2-amino-3-bromoquinolin-7-yl) oxy) methyl) -5- (4-amino-7H-pyrrolo [2,3-d] pyrimidin-7-yl) - 3-methyltetrahydrofuran-3,4-diol (12)
[0305] [0305] A solution of 7 - [[[3aR, 4R, 6R, 6aR) -6- (4-aminopyrrolo [2,3-d] pyrimidin-7-yl) -2,2,3a-trimethyl-6, 6a-dihydro -4H-bore [3,4-d] [1,3] dioxol-4-yl] methoxy] -3-bromo-quinolin-2-amine (12b) (37.0 mg, 0, 07 mmol) in water (1.0 mL) and TFA (1.5 mL, 20.19 mmol) was stirred at 40 ° C for 2 h. LCMS showed that the reaction was complete, the reaction mixture was purified by prep-HPLC, eluted with MeCN in H; O (0.1% NH3-H, 2O) from 10.0% to 95.0% to give (2R, 38, 4R, 5R) -2 - [(2-amino-3-bromo-7 -quinolyl) oxymethyl] -5- (4-aminopyrrolo [2,3-d] pyrimidin-7-yl) -3-methyl-tetrahydrofuran-3,4-diol (Ex. 12) (3.1 mg, 0, 0061 mmol, 8.9% yield) as a white solid. LCMS [M + H]: 501.1 * H NMR (400 MHz, DMSO-d '5 8.29 (s, 1 H), 8.06 (s, 1 H), 7.60 (d, / = 8.8 Hz, 1 H), 7.39 (d, / = 3.6 Hz, 1 H), 6.93-6.99 (m, 4 H), 6.55-6.60 (m, 3 H), 6.16 (d, / = 8.0 Hz, 1 H), 5.11-5.33 (m, 2 H), 4.41 (d, / = 7.6 Hz, 1 H ), 4.17-4.25 (m, 3 H), 1.30 (s, 3 H). 1H NMR (400 MHz, DMSO-d; s + D2O0) 8.30 (s, 1 H), 8.07 (s, 1 H), 7.62 (d / = 84
[0306] [0306] To a solution of compound 1a (19, 2.48 mmol, 1 eq.) In 2,2-dimethoxypropane (12.75 g, 122.42 mmol, 15 ml, 49.44 eq.) Was added TsOH-H2O (141.31 mg, 742.91 pmol 0.3 eq.). The mixture was stirred at 25 ° C for 12 hours. LC-MS showed that compound 1a was maintained. Several new peaks were shown on LC-MS and the desired compound was detected. The reaction was stirred at 60ºC for 2 hours. TLC indicated that compound 1a was consumed completely and new spots were formed. The reaction was cleaned up according to TLC. The reaction was terminated by NaHCO; 3 (20 ml), and extracted with EtO Ac (10 ml * 3). The organic was concentrated in vacuo. The residue was purified by column chromatography (SiO ,, petroleum ether / ethyl acetate = 5/1 to 4: 1). Compound 17a (730 mg, crude) was obtained as a yellow oil. TLC (petroleum ether: Ethyl acetate = 1: 1) R; = 0.79.
[0307] [0307] To a solution of compound 17a (200 mg, 450.57 umol, 1 eq.) In THF (2 ml) was added NH3-H, O (7.28 g, 51.93 mmol, 8.00 ml , 25% purity, 115.26 eq.). The mixture was stirred at 100 ° C for 12 hours in a sealed tube. TLC indicated that compound 17a was completely consumed and new spots were formed. The reaction was cleaned up according to TLC. The mixture was concentrated in vacuo. The residue was purified by means of prep-TLC (SiO ,, petroleum ether: Ethyl acetate = 0: 1). Compound 17b (140 mg, crude) was obtained as a white solid. TLC (petroleum ether: Ethyl acetate = 0: 1) Rr = 0.14.
[0308] [0308] A solution of PPh; 3 (229.26 mg, 874.06 umol, 2 eq.) In THF (4 ml) was added DIAD (176.74 mg, 874.06 pmol, 169.95uL, 2 eq. .) at 0 ° C, the solution was stirred for 10 min at 0 ° C, S-ethanothioic acid (66.53 mg, 874.06 umol, 62.18 μl, 2 eg) was added and compound 17b (140 mg, 437.03 umol, 1 eq.) After the solution was stirred for 10 min at 0 ° C, then the mixture was stirred at 25 ° C for 1 hour. LC-MS showed that compound 17b was completely consumed and a major peak with the desired MS was detected. The mixture was concentrated in vacuo. The residue was purified by means of prep-TLC (SiO ,, petroleum ether: Ethyl acetate = 1: 1). Compound 17c (165 mg, crude) was obtained as a yellow solid. TLC (petroleum ether: Ethyl acetate = 1: 1) R; = 0.05.
[0309] [0309] To a solution of compound 17c (165 mg, 435.99 umol, 1 eq.) In DCM (5 ml) was added TEA (352.95 mg, 3.49 mmol, 485.48 µl, 8 eq. ) and Boc2O (380.62 mg, 1.74 mmol), 400.66 µL, 4 eq.). The mixture was stirred at 25 ° C for 12 hours. LC-MS showed that a major peak with the desired MS was detected. The reaction was terminated by H2O (5 ml), and then extracted with TBME (5 ml x 3), the organic phase was concentrated in vacuo. The crude product compound 17d (252 mg crude) was used in the next step without further purification as a yellow oil. LCMS: (M + H *): 579.2.
[0310] [0310] To a solution of compound 17d (252 mg, 435.48 umol, 1 eq.) In MeOH (2 ml) and THF (2 ml) was added K2CO; 3 (120.37 mg, 870.95 umol, 2 eq.) And Mel (309.06 mg, 2.18 mmol, 135.55 µL, 5 eq.). The mixture was stirred at 25 ° C for 2 hours. LC-MS showed that compound 17d was completely consumed and a major peak with the desired MS was detected. The reaction was filtered and the filtrate was concentrated in vacuo. The residue was purified by means of prep-TLC (SiO ,, petroleum ether: ethyl acetate = 3: 1). The crude product compound 17e (100 mg crude) was used in the next step without further purification as a yellow oil. TLC (petroleum ether: Ethyl acetate = 3: 1) Rr = 0.24.
[0311] [0311] To a solution of compound 17e (100 mg, 221.95 umol, 1 eq.) Was added TFA (3.08 g, 24.31 mmol, 2 ml, 90% purity, 109.53 eq.) . The mixture was stirred at 25ºC for 3 hours. LC-MS showed that compound 17e € was completely consumed and a major peak with the desired MS was detected. The reaction was concentrated in vacuo at 25ºC. The residue was purified by prep-HPLC. Compound 17 (46.96 mg, 135.40 umol, 61.00% yield, 100% purity, HCl salt) was obtained as a white solid. * H NMR (400 MHz, DMSO-d6) 5 = 9.41 (broad s, 1H), 8.80-8.48 (m, 1H), 8.41 (s, 1H), 7.74 (d , | = 3.7 Hz, 1H), 7.06 (d, | = 3.5 Hz, 1H), 6.08 (d, | = 7.9 Hz, 1H), 5.49 (br s, 1H), 4.28 (d, | = 7.7 Hz, 1H), 3.99 (dd, | = 4.3, 8.9 Hz, 1H), 2.85-2.71 (m, 2H ), 2.03 (s, 3H), 1.23 (s, 3H); * H NMR (400 MHz, DMSO-d6 + D 2 O) 5 = 8.38 (s, 1H), 7.73 (d, | = 3.7 Hz, 1H), 7.02 (d, |) = 3.7 Hz, 1H), 6.08 (d, |) = 7.7 Hz, 1H), 4.27 (d, | = 7.9 Hz, 1H), 3.99 (dd, |) = 4.3, 8.9 Hz, 1H), 2.83 - 2.69 (m, 2H), 2.02 (s, 3H), 1.22 (s, 3H); LCMS: (M + H *): 311.1.
[0312] [0312] A mixture of compound 17a (600 mg, 1.35 mmol, 1 eq.) And NH3 in MeOH (7 M, 10 ml, 51.79 eq.) Was stirred at 25 ° C for 12 h. LCMS showed that the desired MS was observed. The mixture was concentrated. The residue was purified by column chromatography (SiO ,, petroleum ether / ethyl acetate = 1/0 to 3: 1). Compound 19a (450 mg, 1.32 mmol, 97.98% yield) was obtained as a white solid. * H NMR (400 MHz, chloroF OR Md) 5 = 8.60 (s, 1H), 7.29 (d, / = 3.7 Hz, 1H), 6.60 (d, / = 3.7 Hz , 1H), 6.17 (d, / = 3.2 Hz, 1H)), 4.74 (d, J = 3.1 Hz, 1H), 4.20 (dd, / = 3.5, 5 , 6 Hz, 1H), 3.89 - 3.71 (m, 2H), 1.61 (s, 3H), 1.57 (s, 3H) 1.38 (s, 3H); LCMS: (M + H *): 340.1.
[0313] [0313] To a mixture of compound 19a (150 mg, 441.47 umol, 1 eq.) And honey (4.56 g, 32.13 mmol, 2 ml, 72.77 eq.) In THF (1 ml) NaH (26.49 mg, 662.21 umol, 60% purity, 1.5 eq.) was added at 0 ° C. The mixture was stirred at 25 for 1 h. TLC showed that compound 19a was consumed and a new main spot was formed. The mixture was finalized by NH solution, saturated ACI (10 ml), extracted with EtOAc (5 ml x 3). The combined organic layers were dried over Na7zSO2, filtered and concentrated. The residue was purified by means of prep-TLC (SiO ,, petroleum ether / ethyl acetate = 2: 1). Compound 19b (140 mg, 395.70 umol, 89.63% yield) was obtained as a white solid. * H NMR (400 MHz, CHLOROPHORMUM-d) 5 = 8.67 (s, 1H), 7.42 (d, = 3.7 Hz, 1H), 6.65 (d, / = 3.7 Hz, 1H), 6.35 - 6.31 (m, 1H), 4.75 (d, / = 2.4 Hz, 1H), 4.26 (dd, / = 4.0.7.1 Hz, 1H ), 3.67 - 3.53 (m, 2H), 3.42 - 3.37 (m, 3H), 1.63 (s, 3H), 1.61 (s, 3H), 1.42 ( s, 3H); LCMS: (M + H *): 354.0; TLC (Petroleum ether / ethyl acetate = 2: 1) Rf = 0.50.
[0314] [0314] A mixture of compound 19b (119.10 mg, 336.64 umol, 1 eq.) And NH3-H2O (47.19 mg, 336.64 pmol, 51.86 µl, 25% purity, 1 eq. .) in dioxane (5 mL) was stirred at 120ºC for 12 h. LCMS showed that compound 19b was consumed and the desired MS was observed. The mixture was concentrated. No further purification. Compound 19c (120 mg, crude) was obtained as a white solid, which was used in the next step with purification. * H NMR (400 MHz, CHLOROPHORMUM-d) 5 = 8.26 (s, 1H), 7.08 (d, / = 3.7 Hz, 1H), 6.36 (d, J = 3.5 Hz , 1H), 6.23 (d, / = 2.2 Hz, 1H), 5.30 (br s, 2H), 4.65 (d, / = 2.4 Hz, 1H), 4.16 ( dd, / = 4.3, 7.2 Hz, 1H), 3.59 - 3.46 (m, 2H), 3.33 (s, 3H), 1.55 (s, 3H), 1.53 (s, 3H), 1.34 (s, 3H); LCMS: (M + H *): 335.1.
[0315] [0315] A mixture of compound 19c (120 mg, 358.88 umol, 1 eq.) And HCI / MeOH (7 M, 1 ml, 19.50 eq.) Was stirred at 25 ° C for 10 min. LCMS showed that compound 19c was consumed and the desired MS was observed. The mixture was concentrated. The residue was purified by prep-HPLC (condition HCl). Compound 19 (50.11 mg, 150.54 umol, 41.95% yield, 99.37% purity, HCI salt) was obtained as a white solid. * H NMR (400 MHz, DMSO-d 6 = 13.66 (s wide, 1H), 9.12 (s wide, 1H), 8.39 (s, 1H), 7.66 (d, / = 3 , 8 Hz, 1H), 7.01 (d, / = 3.7 Hz, 1H), 6.12 (d, / = 7.8 Hz, 1H), 5.40 (br s, 1H), 5 .01 (br s, 1H), 4.19 (d, J = 7.8 Hz, 1H), 3.95 (t / = 3.5 Hz, 1H), 3.57 - 3.42 (m, 2H), 3.34 (s, 3H), 1.24 (s, 3H); “1H 400 MHz MR, DMSO-d6 + D 7 O) ó = 8.36 (s, 1H), 7.65 (d, / = 3.7 Hz, 1H), 6.98 (d, / = 3.7 Hz, 1H), 6.12 (d, / = 7.8 Hz, 1H), 4.18 (d , / = 7.8 Hz, 1H), 3.94 (t) = 3.4 Hz, 1H), 3.57 - 3.39 (m, 2H), 3.33 (s, 3H), 1, 23 (s, 3H); LCMS: (M + H *): 295.2.
[0316] [0316] A mixture of compound 19a (200 mg, 588.63 umol, 1 eq.) And phenol (60.94 mg, 647.49 umol, 56.95 uL, 1.1 eq.) In toluene (1 ml ) was added
[0317] [0317] A mixture of compound 20a (130 mg, 312.60 umol, 1 eq.) And NH3ºH2O (2.73 g, 19.47 mmol, 3 mL, 62.30 eq.) In dioxane (3 mL) stirred at 120ºC for 12 h. LCMS showed that compound 20a was consumed and the desired MS was observed. The mixture was concentrated. The crude product was used in the next step without further purification. Compound 20b (123 mg, crude) was obtained as brown oil. LCMS: (M + H *): 397.2.
[0318] [0318] A mixture of compound 20b (123 mg, 310.26 umol, 1 eq.) And HCI / MeOH (4 M, 4 ml, 51.57 eq.) Was stirred at 25 ° C for 0.5 h. LCMS showed that compound 20b was consumed and the desired MS was observed. The mixture was concentrated. The residue was purified by prep-HPLC (column: UniSil 120 * 30 * 10 um; in the mobile phase: [water (0.05% HCl) - ACNJ; B%: 5% - 35%, 11 min). Compound 20 (4.49 mg, 11.26 umol, 3.63% yield, 98.518% LCMS purity, HCI salt) was obtained as a white solid. * H NMR (400 MHz, DMSO-d 6) 5 = 8.39 (s, 1H), 7.68 (d, / = 3.7 Hz, 1H), 7.37 - 7.25 (m, 2H ), 7.07 - 6.91 (m, 4H), 6.18 (d, / = 7.9 Hz, 1H), 4.38 (d, / = 7.9 Hz, 1H), 4.24 - 4.04 (m, 3H), 1.28 (s, 3H); * H NMR (400 MHz, DMSO-d; + DO) 5 = 8.38 (s, 1H), 7.67 (d,) = 3.7 Hz, 1H), 7.40 - 7.24 (m , 2H), 7.08 - 6.90 (m, 4H), 6.19 (d, / = 7.9 Hz, 1H), 4.38 (d / = 8.2 Hz, 1H), 4, 23 - 4.03 (m, 3H), 1.28 (s, 3H); LCMS: (M + H *): 357.1; 98.52% Purity by LCMS; HPLC purity: 100.00%.
[0319] [0319] A mixture of compound 19a (300 mg, 882.94 umol, 1 eq.) And 3-nitrophenol (122.82 mg, 882.94 umol, 175.46 ul, 1 eq.) In toluene (3 ml ) CMBP (426.20 mg, 1.77 mmol, 2 eq.) was added at 25 ° C under N7. The mixture was stirred at 80 ° C for 12 h under N, TLC showed that compound 19a was consumed and an important new spot was observed. The reaction solution was concentrated. The residue was dissolved in water (15 ml) and the mixture was extracted with EtOAc (10 ml x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by means of prep-TLC (SiO ,, petroleum ether / ethyl acetate = 3/1). Compound 21a (410 mg, crude) was obtained as brown oil. TLC (petroleum ether: Ethyl acetate = 3: 1) Rk = 0.6.
[0320] [0320] A mixture of compound 21a (410 mg, 889.63 umol, 1 eq.), Fe (248.41 mg, 4.45 mmol, 5 eq.) And NHaCI (475.88 mg, 8.90 mmol , 311.03 µl, 10 eq.) In EtoH (5 ml) and HO (1 ml) was stirred at 75 ° C for 1 h. LCMS showed that compound 21a was consumed and the desired MS was observed. The mixture was filtered and concentrated. The residue was dissolved in water (10 ml). The mixture was extracted with EtOAc (5 ml x 4). The combined organic layers were dried over NazSO ,,, filtered and concentrated. The residue was purified by means of prep-TLC (SiO ,, petroleum ether / ethyl acetate = 1/3). Compound 21b (100 mg, 168.91 umol, 26.09% yield) was obtained as a brown oil. 'H NMR (400 MHz, CHLOROPHORM-d) 5 = 8.69 (s, 1H), 7.46 (d, / = 3.8 Hz, 1H), 7.06 (t / = 8.1 Hz, 1H), 6.65 (d, / = 3.7 Hz, 1H), 6.39 (d, / = 2.2 Hz, 1H), 6.32 (ddd, / = 2.4, 5.0 , 7.5 Hz, 2H), 6.24 - 6.20 (m, 1H), 4.86 (d, / = 2.3 Hz, 1H), 4.50 (dd, / = 3.9, 6.5 Hz, 1H), 4.22 (dd, / = 3.8, 10.5 Hz, 1H), 4.10 - 4.05 (m, 1H), 1.66
[0321] [0321] To a mixture of compound 21b (100 mg, 232.08 pmol, 1 eq.) In AcOH (1.6 ml) and H2O (0.2 ml) was added the mixture of potassium cyanate (28.24 mg, 348.12 pmol, 13.71 µl, 1.5 eq.) In H2O (0.3 ml) at 0 ° C. The mixture was stirred at 25 ° C for 12 h. LCMS showed that the compound Lc was consumed and the desired MS was observed. The mixture was finished with a saturated NaHCO solution; until pH = 8-9. The mixture was extracted with EtO Ac (10 ml x 4). The combined organic layers were dried over NazSO;, filtered and concentrated. The residue was purified by means of prep-TLC (SiO>, petroleum ether / ethyl acetate = 1/3). Compound 21c (80 mg, 168.81 umol, 72.74% yield) was obtained as a white solid. * H NMR (400 MHz, CHLOROPHORMUM-d) 5 = 8.70 (s, 1H), 7.44 (d, |) = 3.7 Hz, 1H), 7.25-7.20 (m, 1H ), 7.00 (s, 1H), 6.85 (d, | = 8.2 Hz, 1H), 6.69 - 6.65 (m, 2H), 6.38 (d, | = 2, 2 Hz, 1H), 6.27 (s, 1H), 4.87 (d, | = 2.2 Hz, 1H), 4.60 (wide s, 2H), 4.53 - 4.46 (m , 2H), 4.30 - 4.23 (m, 1H), 1.69 (s, 3H), 1.66 (s, 3H), 1.46 (s, 3H); LCMS: (M + H *): 474.2; TLC (petroleum ether: Ethyl acetate = 1: 3) R; $ = 0.5.
[0322] [0322] A mixture of compound 21c (75 mg, 158.26 umol, 1 eq.) In NH3-ºH2O (910.00 mg, 6.49 mmol, 1 ml, 25% purity, 41.02 eq.) and dioxane (1 mL) was stirred at 60 ° C for 12 h. LCMS showed that compound 21c was maintained and the mixture was stirred at 80 ° C for 2 h. TLC showed that compound 21c was consumed. The crude product was used in the next step without purification. Compound 21d (70 mg, crude) was obtained as a brown solid that was used for the next step without purification. LCMS: (M + H *): 455.2; TLC (petroleum ether: Ethyl acetate = 1: 3) R; = 0.4.
[0323] [0323] A mixture of compound 21d (70 mg, 154.02 umol, 1 eq.) And HCI / MeOH (4 M, 2 ml, 51.94 eq.) Was stirred at 25 ° C for 1h. LCMS showed that compound 21d was consumed and the desired MS was observed. The mixture was concentrated. The residue was purified by prep-HPLC (column: UniSil 120 * 30 * 10 um; in the mobile phase: [water (0.05% HCl) - ACNJ; B%: 1% - 30%, 11 min). Compound 21 (33.54 mg, 74.39 umol, 48.30% yield, LCMS 100% purity, HCl) was obtained as a white solid. H NMR (400 MHz, DMSO-d6) 5 = 8.61 (broad s, 1H), 8.41 (s, 1H), 7.72-7.65 (m, 1H), 7.28 (s , 1H), 7.17-7.11 (m, 1H), 7.01 (br s, 1H), 6.86 (br d, | = 7.9 Hz, 1H), 6.55 (br d , | = 7.3 Hz, 1H), 6.18 (d, | = 7.7 Hz, 1H), 5.84 (wide s, 2H), 4.37 (d, | = 7.7 Hz, 1H), 4.18 (s, 1H), 4.15 - 4.02 (m, 2H), 1.28 (s, 3H); * H NMR (400 MHz, DMSO- d 6 + D 20) ó = 8.39 (s, 1H), 7.67 (d, |) = 3.7 Hz, 1H), 7.26 (s, 1H ), 7.15 (t | = 8.2) Hz, 1H), 6.98 (d, |) = 3.7 Hz, 1H), 6.84 (d, | = 7.9 Hz, 1H) , 6.57 (brd, | = 8.2 Hz, 1H), 6.18 (d, | = 7.9 Hz, 1H), 4.36 (d, | = 7.9 Hz, 1H), 4 , 20 - 4.16 (m, 1H), 4.12 - 4.01 (m, 2H), 1.27 (s, 3H); LCMS: (M + H *): 415.1; 100.00% purity by LCMS; HPLC purity: 100.00%.
[0324] [0324] To a mixture of compound 19a (80 mg, 235.45 umol, 1 eq.) And compound Int-3 (57.83 mg, 259.00 umol, 1.1 eq.) In toluene (2 ml ) CMBP (85.24 mg, 353.18 umol, 1.5 eq.) was added at 25 ° C under N7. LCMS showed that compound 19a was consumed and the desired MS was observed. The mixture was stirred at 80 ° C for 12 h under N2. The mixture was concentrated and the residue was dissolved in water (10 ml). The mixture was extracted with EtOAc (5 ml x 3). The combined organic layers were dried over Na2SO2, filtered and concentrated. The residue was purified by means of prep-TLC (SiO ,, petroleum ether / ethyl acetate = 3/1) to give compound 22a (90 mg, 165.13 pmol, 70.13% yield) as an oil brown. 'H NMR (400 MHz, CHLOROPHORM-d) à = 8.70 (s, 1H), 7.45 (d, / = 3.7 Hz, 1H), 7.26-7.20 (m, 1H) , 6.93-6.73 (m, 4H), 6.66 (d, / = 3.7 Hz, 1H), 6.39 (d, / = 2.2 Hz, 1H), 4.85 ( d) = 2.2 Hz, 1H), 4.50 (dd, / = 3.6, 6.7 Hz, 1H), 4.34 - 4.19 (m, 4H), 1.69 (s, 3H), 1.66 (s, 3H), 1.48 - 1.46 (m, 12H); LCMS: (M + H *): 545.1; Step 2. Preparation of tert-butyl benzylcarbamate 3 - ((((3aR, 4R, 6R, 6aR) -6- (4-amino-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2, 2,3a- trimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl) methoxy) (22b)
[0325] [0325] A mixture of compound 22a (90 mg, 165.13 umol, 1 eq.) And NH3ºH2O (2.73 g, 19.47 mmol, 3 ml, 117.94 eq.) In dioxane (3 ml) stirred at 120ºC for 12 h. LCMS showed that compound 22a was consumed and the desired MS was observed. The mixture was concentrated to give compound 22b (86 mg, crude) as a yellow oil which was used in the next step without further purification. LCMS: (M + H *): 526.2 Step 3. Preparation of (2R, 3S, 4R, 5R) -5- (4-amino-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2 - ((3- (aminomethyl) phenoxy) methyl) -3-methyltetrahydrofuran-3,4-diol (22)
[0326] [0326] A mixture of compound 22b (80 mg, 152.21 umol, 1 eq.) And HCI / MeOH (4 M, 4 ml, 105.12 eq.) Was stirred at 25 ° C for 0.5 h. LCMS showed that compound 22b was consumed and the desired MS was observed. The mixture was concentrated. The residue was purified by prep HPLC (part per column: UniSil 120 * 30 * 10 um; in the mobile phase: [water (0.05% HCl) - ACNJ; B%: 1% - 15%, 11 min, for give the HCl salt, and the other part per column: Agela Durashell C18 150 * 25 5 u; in the mobile phase: [water (0.04% NH3H20) - ACN] J; B%: 5% - 35%, 10 min ) to give the free base.
[0327] [0327] Compound 22 (HCI salt) (7.85 mg, 18.61 umol, 12.22% yield, HCl salt, 100.0% LCMS purity) was obtained as a gray solid. 'H NMR (400 MHz, DMSO-ds) 5 = 8.39 (s, 1H), 8.33 (wide s, 3H), 7.69 (d, / = 3.7 Hz, 1H), 7, 37 (t) = 7.9 Hz, 1H), 7.22 (s, 1H), 7.10 - 7.00 (m, 3H), 6.19 (d, / = 7.9 Hz, 1H) , 5.53 (br s, 1H), 5.21 (s, 1H), 4.39 (d,] = 8.1 Hz, 1H), 4.24 - 4.09 (m, 3H), 4 , 02 (broad d, | = 5.7 Hz, 2H), 1.30 (s, 3H); * H NMR (400 MHz, DMSO-d 6 + D 2 O) 5 = 8.38 (s, 1H), 7.66 (d, J = 3.8 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.17 (s, 1H), 7.10 - 7.03 (m, 2H), 6.98 (d, | = 3.4 Hz, 1H), 6.19 (d, | = 7.9 Hz, 1H), 4.38 (d, | = 8.1 Hz, 1H), 4.24 - 4.08 (m, 3H), 4.05 - 3.98 ( m, 2H), 1.29 (s, 3H); LCMS: (M + H *): 386.2.
[0328] [0328] Compound 22 (free base) (21.67 mg, 55.74 umol, 36.62% yield, 99.13% purity by LCMS) was obtained as a white solid. * 'H NMR (400 MHz, DMSO-ds) 5 = 8.06 (s, 1H), 7.37 (d, / = 3.7 Hz, 1H), 7.22 (tJ) = 7.9 Hz , 1H), 6.99 (broad s, 3H), 6.91 (d, / = 7.5 Hz, 1H), 6.82 (dd, / = 2.3, 8.1 Hz, 1H), 6.60 (d, / = 3.7 Hz, 1H), 6.15 (d, / = 7.9 Hz, 1H)), 5.38 (br s, 1H), 5.01 (br s, 1H), 4.38 (brd, / = 7.6 Hz, 1H), 4.17 - 4.02 (m, 3H), 3.69 (s, 2H), 1.28 (s 3H); 1H NMR (400 MHz, DMSO-d6 + bD20O) δ = 8.05 (s, 1H), 7.35 (d, J = 3.8 Hz, 1H), 7.21 (t) = 7.8 Hz , 1H), 6.98 (s, 1H), 6.90 (d, | = 7.7 Hz, 1H), 6.81 (dd, | = 2.1, 7.9 Hz, 1H), 6 , 59 (d, | = 3.7 Hz, 1H), 6.14 (d, | = 8.1 Hz, 1H), 4.37 (d, | = 81 Hz, 1H), 4.16 - 4 .01 (m, 3H), 3.65 (s, 2H), 1.26 (s, 3H); LCMS: (M + H *): 386.3; Example 26. (2R, 35, 4R, 5R) -5- (4-amino-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2 - ((R) - (4-chlorophenyl) ( hydroxy) methyl) -3-methyltetrahydrofuran-3,4-diol (26) n ATA IF ATL meticoion, EV CIÁO-MmaBr of "X mecNHO of EtoacPiridira - by TT o HF
[0329] [0329] To a mixture of compound 19a (500 mg, 1.47 mmol, 1 eq.), Diacetoxyiodobenzene (DAIB) (1.04 g, 3.24 mmol, 2.2 eq.) In MeCN (2 mL) and HO (2 mL) TEMPO (46.28 mg, 294.31 umol, 0.2 eq.) was added at 0 ° C. The mixture was stirred at 25 for 1 h. TLC showed that compound 19a was consumed. The mixture was concentrated. The residue was dissolved in toluene (10 ml). The mixture was concentrated. The crude product was used in the next step without further purification. Compound 26a (520 mg, crude) was obtained as brown oil. TLC (SiO ,, Ethyl acetate / ethanol = 1/1): R $ = 0.5.
[0330] [0330] To a mixture of compound 26a (520 mg, 1.47 mmol, 1 eq.), N-methoxymethanamine (215.07 mg, 2.20 mmol, 1.5 eq., HCl), pyridine (348, 82 mg, 4.41 mmol, 355.93 ul, 3 eq.) In EtOAc (5 ml) T3P (1.87 g, 2.94 mmol, 1.75 ml, 50% purity, 2 eq.) Was added. ) at 25ºC. The mixture was stirred at 25 ° C for 12 h. TLC showed that compound 26a was consumed. The mixture was finished with water (50 ml) and extracted with EtOAc (25 ml x 3). The combined organic layers were dried over Na7zSO; a, filtered and concentrated. The residue was purified by means of prep-TLC (SiO ,, petroleum ether / ethyl acetate = 1/1). Compound 26b (450 mg, 1.13 mmol, 77.15% yield) was obtained as a colorless oil. * H NMR (400 MHz, CHLOROPHORMUM-d) ô = 8.67 (s, 1H), 8.21 (d, | = 3.7 Hz, 1H), 6.69-6.63 (m, 2H) , 5.26 (s, 1H), 4.60 (d, | = 1.3 Hz, 1H), 3.79 (s, 3H), 3.28 (s, 3H), 1.70 (s, 3H), 1.46 (d, | = 3.5 Hz, 6H); LCMS: (M + H *): 397.2; TLC (SiO>, petroleum ether / ethyl acetate = 1/1): R; = 0.6.
[0331] [0331] To a mixture of compound 26b (200 mg, 504.00 umol, 1 eq.) In THF (2 ml) was added bromo- (4-chlorophenyl) magnesium (1 M, 1.01 ml, 2 eq. ) at -10 ° C under N7, The mixture was stirred at 0 ° C for 1 h under Nx. TLC showed that compound 26b was consumed. The mixture was terminated by NH, CI saturated solution (10 ml), extracted with EtOAc (5 ml x 3). The combined organic layers were dried over NazSO., Filtered and concentrated. The residue was purified by means of prep-TLC (SiO ,, petroleum ether / ethyl acetate = 3/1). Compound 26c (200 mg, 446.13 umol, 88.52% yield) was obtained as a colorless oil. LCMS: (M + H *): 448.1; TLC (SiO ,, petroleum ether / ethyl acetate = 3/1): R $ = 0.6.
[0332] [0332] To a mixture of compound 26c (200 mg, 446.13 umol, 1 eq.) In toluene (2 ml) was added DIBAL-H (1 M, 892.26uL, 2 eq.) At -70 ° C under N2 . The mixture was stirred at -70 ° C for 0.5 h under N 2 TLC showed that compound 26c was consumed. The mixture was finished with water (0.5 ml), 15% NaOH solution (0.5 ml), water (0.5 ml) and the mixture was stirred for 10 min. The mixture was dried over MgSO4, filtered and concentrated. The residue was purified by means of prep-TLC (SiO ,, petroleum ether / ethyl acetate = 3/1). Compound 26d (190 mg, 421.93 umol, 94.57% yield) was obtained as a colorless oil. * H NMR (400 MHz, CHLOROPHORMUM-d) 5 = 8.68 (s, 1H), 7.39-7.30 (m, 5H), 6.68 (d, / = 3.7 Hz, 1H) , 6.19 (d, / = 2.6 Hz, 1H), 4.84 (d, / = 8.4 Hz, 1H), 4.72 (d, | = 2.6 Hz, 1H), 4 , 14 (d, / = 8.4 Hz, 1H), 2.64 (brd, / = 0.7 Hz, 1H), 1.85 (s, 3H), 1.67 (s, 3H), 1 , 43 (s, 3H); TLC (SiO ,, petroleum ether / ethyl acetate = 1/1): Rf = 0.4.
[0333] [0333] A mixture of compound 26d (140 mg, 310.89 umol, 1 eq.) In NH3 * H, 7O (1.59 g, 11.36 mmol, 1.75 mL, 25% purity, 36, 54 eq.) And dioxane (2 ml) were stirred at 100 ° C for 12 h. LCMS showed that compound 26d was consumed and the desired MS was observed. The mixture was concentrated. The crude product was used in the next step without further purification. Compound 26e (133 mg, crude) was obtained as a light yellow oil which was used in the next step without further purification. LCMS: (M + H *): 431.1.
[0334] [0334] A mixture of compound 26e (133 mg, 308.67 umol, 1 eq.) And HCI / MeOH (4 M, 1.77 ml, 22.98 eq.) Was stirred at 25 ° C for 1h. LCMS showed that compound 26e was consumed and the desired MS was observed. The mixture was concentrated. The residue was purified by prep-HPLC (column: Águas Xbridge 150 * 5 u; in the mobile phase: [water (0.04% NH 3H 20 + 10 mM, NH 4 HCO 3) - ACNJ; B%: 10% -40%, 10 min). Compound 26 (56.96 mg, 145.24 umol, 47.05% yield, LCMS 99.65% purity) was obtained as a white solid. * H NMR (400 MHz, DMSO- “6) 5 = 8.04 (s, 1H), 7.45-7.37 (m, 3H), 7.31 (d, | = 8.4 Hz, 2H ), 7.08 (broad s, 2H), 6.63 - 6.55 (m, 2H), 5.84 (d, |] = 8.1 Hz, 1H), 5.24 (d, / = 7.1 Hz, 1H), 4.87 - 4.79 (m, 1H), 4.74 (s, 1H), 4.43 (br t / = 7.5 Hz, 1H), 4.06 ( d, J) = 5.7 Hz, 1H), 1.15 (s, 3H); * H NMR (400 MHz, DMSO-d 6 + D20) 5 = 8.02 (s, 1H), 7.43-7.26 (m, 5H), 6.58 (d, | = 3.5 Hz , 1H), 5.82 (d, | = 8.1 Hz, 1H), 4.79 (d, | = 5.7 Hz, 1H), 4.39 (d, | = 8.2 Hz, 1H ), 4.06 (d, | = 5.7 Hz, 1H), 1.13 (s, 3H); LCMS: (M + H *): 391.0; 99.65% purity by LCMS; HPLC purity: 100.00%.
[0335] [0335] To a solution of compound 19a (150 mg, 441.47 umol, 1 eq.) And compound Int-5 (230 mg, 571.45 umol, 1.29 eq.) In toluene (3 ml) was 2- (tributyl-phosphanylidene) acetonitrile (213.10 mg, 882.94 umol, 2 eq) is added to N ,; at 25ºC. The mixture was stirred at 80 ° C for 12 h. LC-MS showed that compound 19a was maintained. Several new peaks were shown on LC-MS and the desired compound 32a was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by means of prep-TLC (SiO2, petroleum ether / ethyl acetate = 3: 1) and based on TLC (petroleum ether / ethyl acetate = 3: 1, Rf = 0.37). Compound 32a (0.13 g, crude) was obtained as a yellow solid. TLC (petroleum ether: ethyl acetate = 3: 1) R; = 0.37; LCMS: (M + H *): 724.2.
[0336] [0336] To a solution of 32a compound (120 mg, 165.69 umol, 1 eq.) In t-BuOH (2 ml) was added O-methyl hydroxylamine hydrochloride (110.70 mg, 1.33 mmol, 100.64uL, 8 eq.) Under N 2 atmosphere. The mixture was stirred at 80 ° C for 16 h. LC-MS showed that compound 32a was almost consumed. Several new peaks were shown on LC-MS and the desired compound 32b was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was added NaHCO; aq. and extracted with DCM (5 ml x 2) and EtOAc (5 ml x 2), the organic layer was washed with brine (10 ml x 2), dried over Na 4 SO 4, filtered and concentrated under reduced pressure to give a residue . The residue was purified by means of prep-TLC (SiO2, petroleum ether / ethyl acetate = 2: 3, Rf = 0.57) and based on TLC (petroleum ether: ethyl acetate = 2: 3Rf = 0 , 57). Compound 32b (0.1 g, 134.67 umol, 81.28% yield, 98.96% purity) was obtained as a yellow solid. LCMS1). (M + H *): 735.2; TLC (petroleum ether: ethyl acetate = 2: 3) R; = 0.57; LCMS2: (M + H *): 735.5. LCMS purity 98.96%. * H NMR (400 MHz, CHLOROPHORMUM-d) = 7.35-7.44 (m, 6.6 H), 7.28 - 7.33 (m, 3.6 H), 7.19-7, 26 (m, 3 H), 7.01 (s |, 0.7 H), 6.83 - 6.91 (m, 1 H), 6.66 (brd, | = 3.67 Hz, 0, 4 H), 6.39 - 6.52 (m, 1.5 H), 6.25 (s, 0.4 H), 6.04 (d, | = 8.93 Hz, 0.7 H) , 4.81 (s, 0.4 H), 4.66 (s, 0.4 H), 4.42 - 4.58 (m, 0.9 H), 4.18 - 4.39 (m , 1.8 H), 3.88 (d, | = 5.62 Hz, 2.4 H), 1.52 - 1.73 (m, 4.7 H), 1.44 (brd,] = 5.75 Hz, 3 H), 0.80 - 0.93 (m, 1 H).
[0337] [0337] To a solution of compound 32b (0.1 g, 136.08 umol, 1 eq.) Was added TFA (1.54 g, 12.16 mmol, 1 ml, 90% purity, 89.32 eq. .). The mixture was stirred at 25 ° C for 2 h. LC-MS showed that compound 32b was completely consumed and a major peak with the desired product compound 32 was detected. The reaction mixture was added NH3-H2O pH adjusted to about 8 and concentrated under reduced pressure to remove the solvent. The residue was purified by prep-HPLC (basic condition: column: Águas Xbridge 150 * 25 5u; in the mobile phase: [water (0.04% NH3H20 +10 mM NHAaHCO3) - ACNJ; B%: 5% - 35% , 10min). Compound 32 (8.59 mg, 18.25 umol, 13.41% yield, 96.15% purity by LCMS) was obtained as a white solid. * H NMR (400 MHz, DMSO- d 6) 5 = 7.79 (d, J = 8.77 Hz, 0.6 H), 7.54 (d, J = 9.21 Hz, 0.7 H ), 7.48 (s, 0.4 H), 7.21 (d, |) = 3.51 Hz, 0.4 H), 6.92 (brd, |) = 7.45 Hz, 0, 6 H), 6.81 - 6.89 (m, 0.6 H), 6.56 - 6.62 (m, 0.9 H), 6.33 (s, 1.5 H), 6, 25 (d, | = 3.07 Hz, 0.6 H), 6.00 (d, | = 8.33 Hz, 0.4 H), 5.41 (brd, |) = 6.58 Hz, 0.6 H), 4.99 - 5.06 (m, 0.5 H)), 4.33 (t | = 7.89 Hz, 0.4 H), 4.10 - 4.24 (m , 2.2 H), 3.71 (s, 2.2 H), 3.32 (brs, 1.1 H), 1.23 - 1.34 (m, 3 H)); * H NMR (400 MHz, DMSO- d 6 + D 20) 5 = 7.82 (s, 0.3 H), 7.80 (s, 0.3 H), 7.56 (d, | = 9 , 21 Hz, 0.7 H), 7.51 (s, 0.4 H), 7.19 (d, | = 3.07 Hz, 0.4 H), 6.90 - 6.94 (m , 0.7 H), 6.84 - 6.90 (m, 0.7 H), 6.62 (s, 0.3 H), 6.57 - 6.60 (m, 0.6 H) , 6.27 (d, | = 3.07 Hz, 0.5 H), 5.99 (d, | = 7.89 Hz, 0.4 H), 4.33 (d, | = 7.89 Hz, 0.5 H), 4.18 (br s, 0.8 H), 4.14 (wide s, 1.1 H), 4.09 - 4.13 (m, 0.5 H), 1.24 - 1.30 (m, 3 H); LCMS1: (M + H *): 453.2; LCMS: (M + H *): 453.3; 96.15% purity by LCMS; HPLC purity: 100.00%.
[0338] [0338] To a solution of 26b compound (1 g, 2.52 mmol, 1 eq.) In THF (15 ml) was added the compound Int-6 (1 M, 10.08 ml, 4 eq.) A - 10ºC under N2. The mixture was stirred at 0 ° C for 5 min. TLC indicated that compound 26b was completely consumed and many new spots were formed. The reaction was cleaned according to TLC (petroleum ether: Ethyl acetate = 3: 1 Rf = 0.48). To the solution, no. 4 CI (15 mL) was added and extracted with DCM (10 mL x 2). The combined organic layers were washed with brine (20 ml x 2), dried over Na2SOa, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1: 0 to 15: 1) and based on TLC (petroleum ether: ethyl acetate = 3: xf = 0.48). Compound 37a (660 mg, 1.27 mmol, 50.42% yield, 92.94% purity by LCMS) was obtained as a white solid. * H NMR (400 MHz, CHLOROPHORM-d) = 5 8.64 - 8.73 (m, 1 H), 8.28 (d, |] = 2.19 Hz, 1H), 7.99 (dd, | = 8.33, 2.19 Hz, 1 H), 7.89 (d, |) = 3.95 Hz, 1 H), 7.63 (d, | = 8.33 Hz, 1 H), 6.72 (d, |) = 3.95 Hz, 1 H), 6.59 (d, | = 1.32 Hz, 1 H), 5.54 (s, 1 H), 4.70 (d , J) = 1.32 Hz, 1 H), 1.83 (s, 3 H), 1.47 (s, 3 H), 1.36 (s, 3 H); LCMS: (M + H *):
[0339] [0339] To a solution of 37a compound (660 mg, 1.37 mmol, 1 eq.) In toluene (10 ml) was added DIBAL-H (1 M, 2.73 ml, 2 eq.) At -70ºC under N2. The mixture was stirred at -70 ° C for 5 min. TLC indicated that compound 37a was completely consumed and a new spot was formed. The reaction was cleaned according to TLC (petroleum ether: Ethyl acetate = 3: 3xf = 0.30). The reaction solution was added to Salt of seignette (sodium and potassium tartrate) aq. (30 mL) and MTBE (20 mL) stirred at 25ºC for 0.5 h and extracted with MTBE (10 mL x 4), washed with brine (10 mL x 2), dried Na 4 SO 4, filtered and concentrated under reduced pressure to give a residue. the residue was purified by column chromatography (Si02, petroleum ether / ethyl acetate = 1: 0 to 1: 1) and based on TLC (petroleum ether: ethyl acetate = 3: 3rf = 0.30). Compound 37b (310 mg, 513.06 umol, 37.53% yield, 80.23% purity by LCMS) was obtained as a white solid. * H NMR (400 MHz -d) = 5 8.67 (s, 1 H), 7.52 (d, |) = 1.75 Hz, 1 H), 7.40 (d, J = 8.33 Hz, 1 H), 7.31 (d, |) = 3.51 Hz, 1 H), 7.22 (dd, | = 8.33, 1.75 Hz, 1 H), 6.69 (d ,) = 3.95 Hz, 1 H), 6.17 (d, | = 2.63 Hz, 1 H), 4.83 (d, | = 8.33 Hz, 1 H), 4.76 ( d,) = 2.63 Hz, 1 H), 4.05 - 4.18 (m, 1 H), 2.94 (brs, 1 H), 1.84 (s, 3 H), 1.67 (s, 3 H), 1.43 (s, 3H); LCMS: (M + H ”*): 484.3. 80.23% purity by LCMS; TLC (petroleum ether: ethyl acetate = 3: 1) R; = 0.30.
[0340] [0340] To a solution of compound 37b (0.1 g, 206.29 umol, 1 eq.) In tBuOH (1 ml) was added O-methylhydroxylamine hydrochloride (137.83 mg, 1.65 mmol, 125, 30 ul, 8 eq.) Under N; at 25ºC. The mixture was stirred at 80 for 16 h. LC-MS showed that no compound 37b remained. Several new peaks were shown on LC-MS and the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. Compound 37c (100 mg, crude) was used in the next step without further purification as a pink solid. LCMS: (M + H *): 495.4.
[0341] [0341] To a solution of compound 37c (100.00 mg, 201.88 umol, 1 eq.) Was added HCI / MeOH (4 M, 5 ml, 99.07 eq.) At 0 ° C. The mixture was stirred at 25 ° C for 10 min. LC-MS showed that compound 1b was completely consumed and a major peak with the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent at 25 ° C. The residue was added NH3ºH2O at a pH adjusted to about 8. The residue was purified by prep-HPLC (basic condition :, column: Águas Xbridge 150 * 25 5u; in the mobile phase: [water (0.04% NH 3 H2O0 +10 mM NH 4 HCO 3) - ACNJ; B%: 10% - 40%, 10 min). Compound 37 (18.03 mg, 39.00 umol, 19.32% yield, 98.48% purity by LCMS) was obtained as a white solid. * H NMR (400 MHz, DMSO-d 6) 5 = 10.93 (br s, 0.6 H), 10.64 (s |, 0.4 H), 7.43-7.63 (m, 3 H), 7.31-7.40 (m, 1 H), 7.28 (br s, 0.6 H), 6.57 (br s, 0.3 H), 6.24 (br s , 1 H), 5.97 (brs, 1H), 5.78 (brd, | = 8.33 Hz, 0.6 H), 5.30 (br s, 1 H), 4.78 - 4, 88 (m, 1.3 H), 4.74 (br s, 0.6 H), 4.40 (br s, 0.4 H), 4.27 (br s, 0.6 H), 3 , 97 (br d, |) = 6.58 Hz, 0.3 H), 3.89 (br d, | = 7.02 Hz, 0.5 H), 3.65 - 3.79 (m, 3 H), 1.24 (br s, 3 H); * H NMR (400 MHz DMSO-d6 + D20) õ = 7.51 (brd, J = 19.73 Hz, 2.5 H), 7.28 - 7.39 (mM, 1 H),
[0342] [0342] To a solution of compound 17d in MeOH (1 ml) and THF (1 ml) K2CO; 3 was added (95.53 mg, 691.23 umol, 2 eq.) And Honey (245.28 mg, 1 , 73 mmol, 107.58 µL, 5 eq.). The mixture was stirred at 25 ° C for 2 hours. LC-MS showed that compound 17d was completely consumed and a major peak with the desired MS was detected. The reaction was filtered and the filtrate was concentrated in vacuo. The residue was purified by means of prep-TLC (SiO ,, petroleum ether: ethyl acetate = 3: 1). The crude product compound 40a (60 mg, crude) was used in the next step without further purification as a yellow oil. TLC (petroleum ether: Ethyl acetate = 3: 1) R; = 0.24.
[0343] [0343] To a solution of compound 40a (103.11 mg, 221.95 umol, 1 eq.) Was added TFA (3.08 g, 24.31 mmol, 2.00 mL, 90% purity, 109, 53 eq.). The mixture was stirred at 25ºC for 3 hours. LC-MS showed that compound 40a was completely consumed and a major peak with the desired MS was detected. The reaction was concentrated in vacuo at 25ºC. The residue was purified by prep-HPLC. Compound 40 (6.78 mg, 19.77 umol, 8.91% yield, 94.59% purity) was obtained as a white solid. * H NMR (400 MHz, DMSO-d6) 5 = 8.15 (s, 1H), 7.47 (s wide, 1H), 7.35 (s wide, 1H), 6.60 (s wide, 1H ), 6.02 (broad d,) = 7.7 Hz, 1H), 5.32 (brd, | = 6.6 Hz, 1H), 4.90 (s, 1H), 4.30 (brt | = 6.6 Hz, 1H), 3.93 (br s, 1H), 2.95 (br s, 3H), 2.83 - 2.70 (m, 2H), 2.01 (s, 3H) , 1.22 (s, 3H); * H NMR (400 MHz, DMSO-d6 + D; O) ô = 8.13 (s, 1H), 7.33 (d, J = 3.7 Hz, 1H), 6.59 (d, J) = 3.7 Hz, 1H), 6.01 (d, J) = 7.7 Hz, 1H), 4.28 (d, | = 7.9 Hz, 1H), 3.92 (dd, | = 4.2, 8.8 Hz, 1H), 2.93 (s, 3H), 2.80 - 2.67 (m, 2H), 2.00 (s, 3H), 1.21 (s, 3H ); LCMS: (M + H *): 325.1.
[0344] [0344] A mixture of compound 21c (50 mg, 105.51 umol, 1 eq.) In TFA (1 ml) and HO (0.2 ml) was stirred at 25 ° C for 0.5 h. LCMS showed that compound 21c was consumed and the desired MS was observed. The mixture was concentrated. The residue was dissolved in NaHCO; 3 aq. saturated (10 ml) and the mixture was extracted with EtOAc (5 ml x 3). The combined organic layers were dried over Na7SO4; filtered and concentrated. The residue was purified by prep-HPLC (column: Águas Xbridge 150 * 25 5 u; in the mobile phase: [water (0.05% v / v ammonium hydroxide) - ACNJ; B%: 5% - 30%, 11 min). Compound 41 (11.81 mg, 27.22 umol, 25.80% yield, 100% pure base LCMS) was obtained as a white solid. * H NMR (400 MHz, DMSO-d6) 5 = 8.69 (s, 1H), 8.55 (s, 1H), 7.95 (d, | = 3.8 Hz, 1H), 7.25 (s, 1H), 7.14 (t | = 8.1 Hz, 1H), 6.88 (d,) = 8.8 Hz, 1H), 6.77 (d, | = 3.8 Hz, 1H), 6.56 (dd, | = 2.1, 8.2 Hz, 1H), 6.28 (d, | = 7.8 Hz, 1H), 5.85 (s, 2H), 5, 54 (br s, 1H), 5.13 (br s, 1H), 4.45 (br d, | = 7.9 Hz, 1H), 4.24 - 4.02 (m, 3H), 1, 29 (s, 3H); * H NMR (400 MHz, DMSO-d6) 5 = 8.66 (s, 1H), 7.89 (d, | = 3.9 Hz, 1H), 7.22 (s, 1H), 7.15 (t | = 8.1 Hz, 1H), 6.85 (d, | = 8.2 Hz, 1H), 6.76 (d, | = 3.8 Hz, 1H), 6.57 (dd, | = 2.2, 8.2 Hz, 1H), 6.26 (d, | = 7.9 Hz, 1H), 4.43 (d, | = 8.1 Hz, 1H), 4.21 - 4.16 (m, 1H), 4.14 - 4.02 (m, 2H), 1.27 (s, 3H); LCMS: (M + H *): 434.2; 100.00% purity by LCMS; HPLC purity: 100.00%.
[0345] [0345] To a mixture of compound 26a (300 mg, 848.04 umol, 1 eq.), Compound Int-3 (282.76 mg, 1.27 mmol, 1.5 eq.) And pyridine (201.24 mg, 2.54 mmol, 205.35 ul, 3 eq.) in EtO Ac (3 ml) was added to T3P (2.16 g, 3.39 mmol, 2.02 ml, 50% purity, 4 eq. .) at 0ºC under N7. The mixture was stirred at 25 ° C for 12 h. TLC showed that compound 26a was consumed. The mixture was finished with water (10 ml) and extracted with EtOAc (5 ml x 3). The combined organic layers were dried over NazSO., Filtered and concentrated. The residue was purified by means of prep-TLC (SiO ,, petroleum ether / ethyl acetate = 1/1). Compound 42a (360 mg, 645.13 umol, 76.07% yield) was obtained as a brown solid. TLC (SiO>, petroleum ether / ethyl acetate = 1/1): Rf = 0.6; * H NMR (400 MHz, CHLOROPHORMUM-d) δ = 8.70 (s, 1H), 8.50 - 8.37 (m, 1H), 7.47 (s, 1H), 7.42 - 7, 34 (m, 2H), 7.31 - 7.28 (m, 1H), 7.07 (brd, / = 7.6 Hz, 1H), 6.76 (d, / = 3.7 Hz, 1H ), 6.28 (d, / = 2.9 Hz, 1H), 4.88 (br d, / = 2.8 Hz, 2H), 4.71 (s, 1H), 4.29 (brd, / = 5.5 Hz, 2H), 1.81 (s, 3H), 1.69 (s, 3H), 1.45 (s, 12H).
[0346] [0346] A mixture of compound 42a (100 mg, 179.20 umol, 1 eq.) In TFA (2 ml) and H5O (0.2 ml) was stirred at 25 ° C for 12 h. LCMS showed that compound 42a was consumed and the desired MS was observed. The mixture was finished with a saturated NaHCO solution; until pH = 8-9. The mixture was filtered and concentrated. The residue was purified by prep-HPLC (column: Águas Xbridge 150 * 5 u; in the mobile phase: [water (0.04% NH3.H20) - ACN] J; B%: 1% - 30%, 10min). Compound 42 (22.04 mg, 58.56 umol, 32.68% yield, LCMS 97.87% purity) was obtained as a white solid. * H NMR (400 MHz, DMSO-d º 5 = 10.41 (s, 1H), 8.71 - 8.66 (m, 1H), 8.44 (d ,, = 3.7 Hz, 1H) , 7.62 (s, 1H), 7.58 - 7.45 (m, 1H), 7.28 (t | = 7.7 Hz, 1H), 7.09 (d, / = 7.7 Hz , 1H), 6.84 (d, / = 3.5 Hz, 1H),
[0347] [0347] To mix compound 42 (89 mg, 213.00 pmol, 1 eq.) In saturated NaHCO3 solution (5 ml) and dioxane (2 ml) NH3-H2O was added (1.82 g, 12.98 mmol, 2 mL, 25% purity, 60.95 eq.) At 25 ° C. The mixture was stirred at 67 ° C for 12 h. LCMS showed that compound 42 was consumed and the desired MS was observed. The mixture was concentrated. The residue was dissolved in MeCN (10 ml), filtered and concentrated. The residue was purified by prep-HPLC (column: UniSil 120 * 30 * 10 um; in the mobile phase: [water (0.05% HCl) - ACNJ; B%: 1% - 15%, 11 min). Compound 43 (12.61 mg, 26.21 umol, 12.31% yield, LCMS 97.98% purity, 2HCI) was obtained as a white solid. * H NMR (400 MHz, DMSO-d 9º 5 = 10.66 (s, 1H), 8.49-8.32 (m, 5H), 8.16 (d, y = 3.7 Hz, 1H) , 7.82 (s, 1H), 7.58 (br d, | = 8.2 Hz, 1H), 7.41 (t, = 7.8 Hz, 1H), 7.29 - 7.23 ( m, 1H), 7.09 (d, | = 3.7 Hz, 1H), 6.29 (d, |) = 7.9 Hz, 1H), 5.92 - 5.28 (m, 2H) , 4.60 (s, 1H),
[0348] [0348] A mixture of compound 26d (130 mg, 288.69 umol, 1 eq.) And O-methylhydroxylamine hydrochloride (192.88 mg, 2.31 mmol, 175.35 ul, 8 eq.) In t BuOH (3 mL) was stirred at 80 ° C for 12 h. LCMS showed that compound 6d was consumed and the desired MS was observed. The mixture was concentrated. Compound 44a (133 mg, 288.56 umol, 99.96% yield) was obtained as a white solid which was used in the next step without further purification. LCMS: (M + H *): 461.1.
[0349] [0349] A mixture of compound 44a (133.00 mg, 288.56 umol, 1 eq.) And HCI / MeOH (4 M, 2.00 ml, 27.72 eq.) Was stirred at 25 ° C for 1h. LCMS showed that compound 44a was consumed. The mixture was concentrated. The residue was purified by prep-HPLC (column: Águas Xbridge 150 * 25 5 u; in the mobile phase: [water (0.04% NH 3H 20 +10 mM NH 4 HCO 3) - ACNJ; B%: 10% - 40%, 10 min). Compound 44 (28.44 mg, 65.98 umol, 22.87% yield, 97.6% purity by LCMS) was obtained as an off-white solid. * H NMR (400 MHz, DMSO-d 6) 5 = 11.13-10.34 (m, 1H), 8.12 (br s, 0.2H), 7.59 - 7.20 (m, 5H ), 6.58 (brd, / = 3.1 Hz, 0.3H), 6.31 - 6.10 (m, 0.8H), 6.03 - 5.70 (m, 1H), 5, 34 - 5.17 (m, 1H), 4.85 - 4.70 (m, 2H), 4.39 (br s, 0.3H), 4.26 (brt / = 7.5 Hz, 0, 5H), 4.02 (br d, J = 6.4 Hz, 0.4H), 3.95 (br d, / = 6.8 Hz, 0.6H), 3.78 - 3.70 (m , 3H) 1.30 - 1.17 (m, 3H); * H NMR (400 MHz, DMSO-d 6 + D 2 0) 5 = 8.08 (br s, 0.2H), 7.54 - 7.12 (m, 5H), 6.57 (d, | = 3.5 Hz, 0.3H), 6.27 (d, | = 3.4 Hz, 0.5H), 5.91 (brd, | = 8.2 Hz, 0.3H), 5.74 (d, | = 8.2 Hz, 0.5H), 4.81 - 4.63 (m, 1H), 4.35 (br d, |) = 8.3 Hz, 0.3H), 4, 23 (d, |) = 8.1 Hz, 0.6H), 4.03 (brd, | = 6.2 Hz, 0.3H), 3.96 (d, | = 7.0 Hz, 0, 5H), 3.77 - 3.64 (m, 3H), 1.19 (s, 3H); LCMS: (M + H *): 421.1; 97.64% purity by LCMS; HPLC purity: 98.24%.
[0350] [0350] To a solution of compound 19a (0.2 g, 588.63 umol, 1 eq) and Int-2 compound (158.58 mg, 882.94 umol, 1.5 eq.) In toluene (4 mL) 2- (tributyl-phosphanylidene) acetonitrile (284.13 mg, 1.18 mmol, 2 eq.) was added under N2 at 25 ° C. The mixture was stirred at 80 ° C for 10 h. LC-MS showed that compound 19a was maintained. Several new peaks were shown on LC-MS and the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by prep-TLC (SiO2, petroleum ether / ethyl acetate = 3: 1) and based on TLC (Plate 1 Petroleum ether / ethyl acetate = 3: 1 Rf = 0.21) . Compound 45a (220 mg, crude) was obtained as a white solid. LCMS: (M + H *): 501.1; TLC (petroleum ether: ethyl acetate = 3: 1) R; = 0.21.
[0351] [0351] To a solution of compound 45a (0.22 g, 438.81 umol, 1 eq.) In t-BuOH (1 ml) was added O-methylhydroxylamine hydrochloride (293.18 mg, 3.51 mmol, 266.53 ul, 8 eq Under N ;; at 25 ° C. The mixture was stirred at 80 ° C for 12 h. LC-MS showed that no compound 1c remained. The reaction mixture was concentrated under reduced pressure to remove the solvent. was added to sat. NaHCO3 aq. and extracted with DCM (5 ml x 2) and EtOAc (5 ml x 2) The organic layer was washed with brine (10 ml x 2), dried over Na2S04, filtered and concentrated under pressure reduced to give a residue.The residue was purified by prep-HPLC (basic condition: column: YMC-Actus Triart C18 100 * 30 mm * 5 µm; mobile phase: water (0.04% NH3H, O at 10 mM
[0352] [0352] A mixture of compound 26d (80 mg, 177.65 umol, 1 eq.) And hydroxylamine (11.74 mg, 177.65 umol, 2 ml, 50% purity, 1 eq.) In dioxane (2 mL) was stirred at 100 ° C for 12 h. LCMS showed that compound 26d was consumed and the desired MS was observed. The mixture was concentrated. Compound 46a (79 mg, crude) was obtained as brown oil, which was used for the next step without further purification. LCMS: (M + H *): 447.1.
[0353] [0353] A mixture of compound 46a (79.00 mg, 176.78 umol, 1 eq.) And HCIMeOH (4 M, 2 ml, 45.25 eq.) Was stirred at 25 ° C for 1h. LCMS showed that compound 1f was consumed and the desired MS was observed. The mixture was concentrated. The residue was purified by prep-HPLC (column: UniSil 120 * 30 * 10 um; in the mobile phase: [water (0.05% HCl) - ACNJ; B%: 5% - 30%, 11 min). Compound 46 (17.12 mg, 38.08 umol, 21.54% yield, LCMS 98.587% purity, HCl) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d 6) 5 = 10.99 (br s, 1H), 8.26 (s, 1H), 7.83 (br d, / = 3.1 Hz, 1H), 7 , 42 - 7.35 (m, 2H), 7.33 - 7.26 (m, 2H), 6.87 (br s, 1H), 6.01 (d, / = 8.1 Hz, 1H) , 4.77 (d, | = 7.6 Hz, 1H), 4.32 (d, J] = 8.1 Hz, 1H), 3.98 (d, | = 7.6 Hz, 1H), 1.32-1.19 (m, 3H); IH NMR (400 MHz, DMSO-d 6 + D20) 5 = 8.28 (s, 1H), 7.79 (d, J = 3.7 Hz, 1H), 7.41-7.25 (m, 4H), 6.82 (d, | = 3.7 Hz, 1H), 6.01 (d, |) = 8.1 Hz, 1H), 4.74 (d, |) = 7.5 Hz, 1H), 4.30 (d, | = 8.1 Hz, 1H), 3.99 (d, | = 7.5 Hz, 1H), 1.30 - 1.19 (m, 3H); LCMS: (M + H *): 407.1; 98.59% purity by LCMS; HPLC purity: 99.35%.
[0354] [0354] To a solution of compound 37b (90 mg, 185.66 umol, 1 eq.) In dioxane (5 ml) was added NH3-H2O (26.03 mg, 185.66 pmol, 28.60 uL, 25 % purity, 1 eq.) at 25ºC. The mixture was sealed and stirred at 100 ° C for 12 h (30 psi). LC-MS showed that compound 37b was completely consumed and a major peak with the desired product was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. Compound 47a (80 mg, crude) was used in the next step without further purification as a yellow solid.
[0355] [0355] To a solution of Compound 47a (80 mg, 171.92 umol, 1 eq.) HCI / MeOH was added (4 M, 4.26 ml, 99.07 eq.) At 0 ° C. The mixture was stirred at 25 ° C for 10 min. LC-MS did not show that Compound 47a remained. Several new peaks were shown on LC-MS and the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was added to NH3-H2O at a pH adjusted to about
[0356] [0356] For (2R, 3S, 4R, 5R) -5- (4-aminopyrrolo [2,3-d] pyrimidin-7-yl) - 2 - [(R) - (3,4-dichlorophenyl) -hydroxy -methyl] -3-methyl-tetrahydrofuran-3,4-diol (100.mg, 0.24 mmol) in IPA (5 mL) was sonicated at 50 ° C to obtain a clear solution and then sulfuric acid was added (2.14 mL, 0.24 mmol)) and sonicated at 50 ° C for 5 minutes. The mixture was cooled slowly and the solid obtained was centrifuged, washed with a minimum amount of water and dried under high vacuum to give 95 mg of needle-like crystals; m.p. 216-219ºC. * H NMR (500 MHz, DMSO-d6) 5 8.21 (s, 1H), 7.65 (d, J = 3.7 Hz, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.51 (d, | = 8.3 Hz, 1H), 7.37 (dd, | = 1.9, 8.3 Hz, 1H), 6.79 (d, | = 3.6 Hz,
[0357] [0357] To a mixture of compound 26b (1 g, 2.52 mmol, 1 eq.) In THF (10 ml) the compound Int-7 was added (0.5 M, 15.12 ml, 3 eq.) at 25 ° C under N2 .. The mixture was stirred at 25 ° C for 0.5 h under N2. TLC showed that compound 26b was consumed. The mixture was completed by saturated NaHCO3 solution (3 ml). The mixture was extracted with EtOAc (10 ml x 3). The combined organic layers were dried over Na7zSO; a, filtered and concentrated. The residue was purified by column chromatography (SiO ,, petroleum ether / ethyl acetate = 100/1 to 30/1). Compound 49a (900 mg, 1.97 mmol, yield of
[0358] [0358] To a mixture of compound 49a (200 mg, 436.81 umol, 1 eq.) In toluene (2 ml) DIBAL-H was added (1 M, 873.62uL, 2 eq.) At -7 / 0ºC under N>. The mixture was stirred at -70 ° C for 0.5 h under N 7 TLC showed that compound 49a was consumed. The mixture was finished with water (0.5 ml), 15% NaOH solution (0.5 ml), water (0.5 ml) and the mixture was stirred for 10 min. The mixture was dried over MgSO;, filtered and concentrated. The residue was purified by means of prep-TLC (SiO ,, petroleum ether / ethyl acetate = 1/1). Compound 49b (190 mg, 413.15 umol, 94.58% yield) was obtained as a white solid. * H NMR (400 MHz, CHLOROPHORUM-d) ô = 8.67 (s, 1H), 7.33 (d, /) = 3.8 Hz, 1H), 6.93 (d, / = 1.6 Hz, 1H), 6.89-6.84 (m, 1H), 6.79 - 6.74 (m, 1H), 6.67 (d, = 3.7 Hz, 1H), 6.24 ( d, / = 2.4 Hz, 1H), 5.95 (s, 2H), 4.73 (dd, / = 2.8, 8.7 Hz, 1H), 4.67 (d, /) = 2.3 Hz, 1H), 4.15 - 4.09 (m, 1H), 2.31 (d, / = 2.8 Hz, 1H), 1.86 (s, 3H), 1.68 ( s, 3H), 1.44 (s, 3H); TLC (SiO>, petroleum ether / ethyl acetate = 1/1): Rs = 0.4.
[0359] [0359] A mixture of compound 49b (150 mg mg, 326.17 umol, 1 eq.), CS 2 (1.74 g, 22.83 mmol, 1.38 ml, 70 eq.) And Honey (3, 24 g, 22.83 mmol, 1.42 mL, 70 eq.) In THF (3 mL) was stirred at 0 ° C for 0.5 h under N 2. NaH (27.40 mg, 684.96 umol, 60% of purity, 2.1 eq.) was added at 0 ° C under N2. The mixture was stirred at 0 ° C for 0.5 h. LCMS showed that compound 49b was consumed and the desired MS was observed. The mixture was finalized by NH, saturated aCl solution (10 mL), extracted with EtOAc (5 mL x 3). The combined organic layers were dried over NazSO., Filtered and concentrated. The residue was purified by means of prep-TLC (SiO ,, petroleum ether / ethyl acetate = 5/1). Compound 49c (160 mg, crude) was obtained as a white solid. * H NMR (400 MHz, CHLOROPHORMOM - d) 5 = 8.69 (s, 1H), 7.30 (br d, / = 3.8 Hz, 2H), 6.74 (s, 1H), 6, 69 (s, 2H), 6.51 (d, / = 9.7 Hz, 1H), 6.30 - 6.18 (m, 1H), 5.92 (s, 2H), 4.84 (s , 1H), 4.60 - 4.48 (m, 1H), 2.58 (s, 3H), 1.71 (s, 3H), 1.66 (s, 3H), 1.45 (s, 3H); LCMS: (M + H ”*): 550.1; TLC (SiO ,, petroleum ether / ethyl acetate = 5/1): R; = 0.5.
[0360] [0360] A mixture of compound 49c (150 mg mg, 272.70 umol, 1 eq.), BuzSnH (396.87 mg, 1.36 mmol, 360.79 ul, 5 eq.) And AIBN (134.34 mg, 818.11 umol, 3 eq.) in toluene (2 mL) was stirred at 120 ° C for 0.5 h. LCMS showed that compound 49c was consumed and the desired MS was observed. The mixture was concentrated. The residue was purified by means of prep-TLC (SiO>, petroleum ether / ethyl acetate = 3/1). Compound 49d (45 mg, 101.38 umol, 37.18% yield) was obtained as a white solid. Compound 1f (20 mg, crude) was obtained as a yellow oil. Cpd LCMS. 49d: (M + H *): 444.0; Cpd LCMS. 49e: (M + H *): 410.0; TLC (SiO>, petroleum ether / ethyl acetate = 3/1): Rr (cpd. 1e) = 0.4 &R; (cpd. 1f) = 0.3.
[0361] [0361] A mixture of compound 49d (45 mg, 101.38 umol, 1 eq.) In NH3-H2O (1.82 g, 12.98 mmol, 2 ml, 25% purity, 128.06 eq.) and dioxane (2 mL) was stirred at 100 ° C for 12 h. LCMS showed that compound 49d was consumed. The mixture was concentrated. The crude product was used in the next step without further purification. Compound 49f (43 mg, crude) was obtained as a yellow solid. LCMS: (M + H *): 425.1; TLC (SiO ,, petroleum ether / ethyl acetate = 5/1): Rr = 0.0.
[0362] [0362] A mixture of compound 49f (40 mg, 94.24 umol, 1 eq.) And HCI / MeOH (4 M, 2 ml, 84.89 eq.) Was stirred at 25 ° C for 1h. LCMS showed that compound 49f was consumed. The mixture was concentrated. The residue was purified by prep-HPLC (column: Águas Xbridge 150 * 25 5 u; in the mobile phase: [water (0.04% NH 3H 20 +10 MM NHaHCO3) - ACNJ; B%: 5% - 25% , 10 min). Compound 49 (2.43 mg, 6.26 umol, 6.65% yield, LCMS 99.063% purity) was obtained as a white solid. * H NMR (400 MHz, DMSO-, g 6) = 8.04 (s, 1H), 7.44 (d, J = 3.5 Hz, 1H), 7.00 (wide s, 2H), 6 , 75-6.67 (m, 2H), 6.66 - 6.59 (m, 2H), 5.97 (d, = 7.7 Hz, 1H), 5.88 (dd, / = 0, 8, 5.4 Hz, 2H), 5.33 (d, / = 6.8 Hz, 1H), 4.82 (s, 1H), 4.37 (t) = 7.3 Hz, 1H), 3.93 (dd, / = 3.4, 10.7 Hz, 1H), 2.88 - 2.72 (m, 2H), 1.25 (s, 3H); * H NMR (400 MHz DMSO-d 6 + D20) 5 = 8.02 (s, 1H), 7.42 (d, / = 3.7 Hz, 1H), 6.73-6.57 (m, 4H), 5.95 (d, / = 7.7 Hz, 1H), 5.84 (d, / = 3.7 Hz, 2H), 4.35 (d,) = 7.7 Hz, 1H) , 3.92 (dd, / = 5.0, 9.4 Hz, 1H), 2.82 - 2.72 (m, 2H) 1.25 (s, 3H);
[0363] [0363] To a solution of compound 37b (150 mg, 309.43 umol, 1 eq.) In THF (3 ml) CS 2 was added (1.65 g, 21.66 mmol, 1.31 ml, 70 eq. .) and Honey (3.07 g, 21.66 mmol, 1.35 mL, 70 eq.). The mixture was stirred at 0 ° C for 10 min. The mixture was added to NaH (25.99 mg, 649.81 umol, 60% pure, 2.1 eq.) And stirred at 0 ° C for 0.5 h. LC-MS showed that compound 37b was consumed. Several new peaks were shown on LC-MS and the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H2 O (15 ml) and extracted with EtOAc (15 ml x 3). The combined organic layers were washed with brine (25 ml x 2), dried over Na2SOa, filtered and concentrated under reduced pressure to give a residue. The residue was purified by means of prep-TLC (SiO2, petroleum ether / ethyl acetate = 3: 1) and based on TLC (petroleum ether / ethyl acetate = 3/1, Rf = 0.61). Compound 50a (150 mg, 240.79 umol, 77.82% yield, 92.29% purity) was obtained as a white solid. TLC (petroleum ether: Ethyl acetate = 3: 1) R; = 0.61; LCMS1: (M + H *): 575.7; LCMS 2: (M + H *): 575.8, 92.29% purity by LCMS.
[0364] [0364] To a solution of compound 50a (70 mg, 121.75 umol, 1 eq.) In toluene (1 ml) AIBN was added (6.00 mg, 36.53 umol, 0.3 eq.) And Bu 3 SnH (220.00 mg, 755.86 µmol, 200.00 µl, 6.21 eq.) Under N; at 25ºC. The mixture was stirred at 110 ° C for 1 h. LC-MS showed that no compound 50a was maintained. Several new peaks were shown on LC-MS and the desired compounds 50b and 50c were detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by means of prep-TLC (SiO ,, petroleum ether: ethyl acetate = 3: 1) and based on TLC (petroleum ether: ethyl acetate = 3: 1, ns (cpd. 50b) = 0.54, R; (cpd. 500) = 0.21 Compound 50b (40 mg, crude) was obtained as a colorless oil Compound 50c (10 mg, crude) was obtained as a colorless oil. cpd. 50b: (M + H *): 470.1; cpd. 50c LCMS: (M + H *): 434.0, 79.33% purity by LCMS.
[0365] [0365] To a solution of compound 50b (40 mg, 85.33 19.47 mmol 1 eq.) In dioxane (5 ml) was added NH3-H2O (2.73 g, 19.47 mmol, 3 ul, 25 % purity, 228.19 eq.) at 25ºC. The mixture was sealed and stirred at 100 ° C for 10 h (30 psi). LC-MS showed that compound 50b was completely consumed and a major peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. Compound 50d (40 mg, crude) was used in the next step without further purification as a yellow solid. LCMS: (M + H *): 449.3.
[0366] [0366] To a solution of compound 50d (80 mg, 178.04 umol, 1 eq.) HCI / MeOH was added (4 M, 4.64 ml, 104.24 eq.) And stirred at 25 ° C for 5 min. LC-MS showed that no 50d compound remained. Several new peaks were shown on LC-MS and the desired compound 50 was detected. The reaction mixture was added NH3 + H2O the pH was adjusted to about 8 and concentrated under reduced pressure to remove the solvent at 25 ° C. The residue was purified by preparative HPLC (basic condition: column: Águas Xbridge 150 * 25 5u; in the mobile phase: [water (0.04% NH2H20 + 10 mM NH 3 HCO 3) —J; B%: 10% - 40%, 10 min). Compound 50 (20.04 mg, 48.84 umol, 27.43% yield, 99.75% purity) was obtained as a white solid. LCMS1: (M + H *): 409.3; * H NMR (400 MHz, DMSO-d 5) 5 = 8.05 (s, 1 H), 7.42 - 7.49 (m, 3 H), 7.17 (dd, / = 8.38, 1.98 Hz, 1 H), 7.00 (s, 2 H), 6.63 (d, | = 3.75 Hz, 1 H), 5.98 (d, / = 7.72 Hz, 1 H), 5.37 (d, / = 6.84 Hz, 1 H), 4.88 (s, 1 H), 4.42 (t / = 7.39 Hz, 1 H), 4.00 ( dd, / = 11.25, 3.09 Hz, 1 H), 2.93 - 3.02 (m, 1 H), 2.84 - 2.91 (m, 1 H), 1.27 (s , 3H); * H NMR (400 MHz, DMSO-d & + D 2 0) 5 = 8.03 (s, 1 H), 7.37 - 7.45 (m, 3 H), 7.16 (dd) = 8 , 27, 1.87 Hz, 1 H), 6.63 (d, | = 3.53 Hz, 1 H), 5.96 (d, / = 7.94 Hz, 1 H), 4.39 ( d, / = 7.94 Hz, 1 H), 3.99 (dd, / = 10.80, 3.53 Hz, 1H), 2.78 - 3.00 (m, 2H), 1.27 ( s, 3H); LCMS2: (M + H *): 409.0; 99.75% purity by LCMS; HPLC purity: 100.00%.
[0367] [0367] To a solution of compound 50c (20 mg, 46.05 umol, 1 eq.) HCI / MeOH was added (4 M, 1.20 ml, 104.24 eq.) And stirred at 25 ° C for 5 min. LC-MS showed that no 50c compound remained. Several new peaks were shown on LC-MS and the desired compound 51 was detected. The reaction mixture was added NH3-H2O the pH was adjusted to about 8 and concentrated under reduced pressure to remove the solvent at 25 ° C. The residue was purified by preparative HPLC (basic condition: column: Águas Xbridge 150 * 25 5u; in the mobile phase: [water (0.04% NH 3 H 20 + 10 MM NH 4 HCO 3) - ACN] J; B %: 15% - 45%, min). Compound 51 (2.31 mg, 5.44 umol, 11.82% yield, 92.89% purity by LCMS) was obtained as a white solid. LCMS1: (M + H *): 394.3; * H NMR (400 MHz, DMSO-ds) 5 = 9.03 (s, 1 H), 8.81 - 7.49 (m, 1 H), 8.00 (dd, / = 8.38, 1H ), 7.41 (s, 2H), 7.18 (d, | = 1.98 Hz, 1 H), 6.76 (d, / = 3.75 Hz, 1 H), 6.16 (d , / = 6.84 Hz, 1 H), 4.98 (s, 1 H), 4.50 (t / = 7.28 Hz, 1 H), 4.07 (dd, / = 11.14, 3.20 Hz, 1 H), 2.96 - 3.08 (m, 1 H), 2.83 - 2.95 (m, 1 H), 1.30 (s, 3H); * H NMR (400 MHz, DMSO-d; + D 2 0) 5 = 8.99 (s, 1 H), 8.76 - 7.45 (m, 3 H), 7.90 (dd) = 3 , 75 Hz8.27, 7.37 (, 1 H), 7.40 (d, | = 7.89 Hz, 1 H), 7.37 (d, / = 8.33 Hz, 1 H), 6 , 77 (d, / = 3.51 Hz, 1 H), 6.12 (dd, / = 7.89 Hz, 1, 4.02 - 4.08 (, 1H), 4.02 - 4.08 (m, 2H), 2.88 (s, 3H); LCMS2: (M + H *): 394.0; 92.89% purity by LCMS; HPLC purity: 95.16%.
[0368] [0368] A mixture of compound 49e (20 mg, 48.85 umol, 1 eq.) And HCI / MeOH (4 M, 2 ml, 163.77 eq.) Was stirred at 25 ° C for 1h. LCMS showed that compound 49e was consumed. The mixture was concentrated. The residue was purified by prep-HPLC (column: Águas Xbridge 150 * 25 5 u; in the mobile phase: [water (0.04% NH 3H 20 +10 mM NH 4 HCO 3) - ACNJ; B%: 10% - 40%, 10 min). Compound 52 (5.25 mg, 14.08 umol, 28.83% yield, LCMS 99.078% purity) was obtained as a white solid. * H NMR (400 MHz, DMSO-d 6 5 = 9.02 (s, 1H), 8.80 (s, 1H), 7.97 (d, |] = 3.7 Hz, 1H), 6, 76 (d, / = 3.7 Hz, 1H), 6.74 - 6.69 (m, 2H), 6.63 (d, / = 8.1 Hz, 1H), 6.15 (d, / = 7.8 Hz, 1H), 5.88 (d J = 4.3 Hz, 2H), 5.43 (br s, 1H), 4.93 (br s, 1H), 4.47 (d, / = 7.7 Hz, 1H), 4.01 (dd) = 3.2, 10.8 Hz, 1H), 2.93 - 2.76 (m, 2H), 1.28 (s 3H); * H NMR (400 MHz, DMSO-d6 + D20) δ = 8.99 (d, J = 2.3 Hz, 1H), 8.75 (d, J = 2.1 Hz, 1H), 7.87 (d, J = 2.8 Hz, 1H), 6.79 - 6.74 (m, 1H), 6.71 - 6.58 (m, 3H), 6.11 (dd, | = 2.3 , 7.8 Hz, 1H), 5.82 (brd,) = 2.6 Hz, 2H), 4.43 (dd, | = 2.8, 7.9 Hz, 1H), 2.86-2 , 74 (m, 2H), 1.27 (brs, 3H); LCMS: (M + H *): 370.1; 99.078% purity by LCMS; HPLC purity: 100.00%.
[0369] [0369] To a solution of TEA (0.12 mL, 0.88 mmol) and Tosil chloride (112.2 mg, 0.59 mmol) in DCM (15.0 mL) was added [(3aR, 4R, 6R, 6aR) -6- (4-chloropyrrolo [2,3-d] pyrimidin-7-yl) -2,2,3a-trimethyl -6,6a-dihydro-4H-bore [3,4-d ] [1,3] dioxol-4-yl] methanol (19a) (100.0 mg, 0.29 mmol) and DMAP (35.9 mg, 0.29 mmol). The reaction mixture was stirred at 35 ° C for 1 h. LCMS showed that the reaction was completed. The mixture was diluted with DCM (50.0 ml) and washed with brine (20.0 ml x 3), dried over Naz2S Ou, filtered and concentrated in vacuo to give the crude product which was purified by gel column chromatography silica (AE: MeOH = 50: 1 to provide [(3aR, 4R, 6R, 6aR) -6 - (4-chloropyrrolo [2,3-d] pyrimidin-7-yl) -2,2,3a-trimethyl- [3,4-d] [1,3] dioxol-4-yl] methyl (53a) 6,6a-dihydro-4H-furo 4-methylbenzenesulfonate (53a) (150.0 mg ,, 29 mmol, yield 99 , 1% LCMS [M + H] J: 494.1
[0370] [0370] To a solution of [(3aR, 4R, 6R, 6aR) -6 - (4-chloropyrrolo [2,3-d] pyrimidin-7-yl) -2,2,3a-trimethyl-6,6a- [3,4-d] [1,3] dioxol-4-yl] methyl dihydro-4H-furo 4-methylbenzenesulfonate (53a) (150.0 mg, 0.30 mmol) in DMF (10.0 mL) Cs2CO; 3 was added (296.8 mg, 0.91 mmol) and quinolin-7-ol (44.1 mg, 0.30 mmol). The reaction mixture was stirred at 80 ° C for 16 h under N2. The reaction mixture was concentrated in vacuo and diluted with EtOAc (10.0 ml). The mixture was washed with brine (10.0 mL X 2), dried over NazSOau, filtered and concentrated in vacuo to give the crude product which was purified by pre-TLC (MeOH: DCM = 1: 15) to provide 7 - [ [[3aR, 4R, 6R, 6aR) -6- (4-chloropyrrolo [2,3-d] pyrimidin-7-yl) -2,2,3a-trimethyl-6,6a-dihydro-4H-bore [3 , 4-d] [1,3] dioxol-4-yl] methoxy] quinoline (53b) (30.0 mg, 0.06 mmol, 19.9% yield). LCMS [M + H]: 466.9.).
[0371] [0371] A solution of 7 - [[[3aR, 4R, 6R) -6- (4-chloropyrrolo [2,3-d] pyrimidin-7-yl) -2,2,3a-trimethyl-6,6a- dihydro-H-hole [3,4-d] [1,3] dioxol-4-yl] methoxy] quinoline (30.0 mg, 0.06 mmol) in 1,4-dioxane (5.0 mL) and ammonium hydroxide (5.0 mL, 129.81 mmol) was stirred at 120ºC for 18 h in a sealed tube. TLC (PE: EA = 1: 1, Rf = 0.1) showed that the reaction was complete. The reaction mixture was concentrated in vacuo to 7 - [(3aR, 4R, 6R, 6aR) -2,2,3a-trimethyl -4- (7-quinolyloxymethyl) -6,6a-dihydro-4H-furo- [3, 4-d] [1,3] dioxol-6-yl] pyrrolo [2,3-d] pyrimidin-4-amine (53c) (29.9 mg, 0.07 mmol) which was used directly in the next step.
[0372] [0372] A mixture of 7 - [(3aR, 4R, 6R, 6aR) -2,2,3a-trimethyl-4- (7-quinolyloxymethyl) -6,6a-dihydro-4H-bore - [3,4- d] [1,3] dioxol-6-yl] pyrrole [2,3-d] pyrimidin-4-amine (29.9 mg, 0.07 mmol), water (3.0 mL) and TFA (0, 2 mL, 2.73 mmol) were stirred at 40 ° C for 2 h. LCMS showed that the reaction was completed. The reaction mixture was purified by prep-HPLC, eluted with MeCN in H 2 O (0.1% NH 3 * 120) from 10.0% to 95.0% to give (2R, 35, 4R, 5R) -5- (4-aminopyrrolo [2,3-d] pyrimidin-7-yl) -3-methyl-2- (7-quinolyloxymethyl) tetrahydrofuran-3,4-diol (Ex. 53) (3.0 mg, 0.007 mmol, 11.0% yield) as a white solid. LCMS [M + HJ]: 408.2.). * H NMR (400 MHz, DMSO- 46) 5 8.66 (s, 1 H), 8.29 (s, 1 H), 7.79 (d, / = 3.6 Hz 1 H), 7, 60 (d, / = 8.4 Hz, 1 H), 6.94-6.98 (m, 2 H), 6.77 (d, / = 3.2 Hz, 1 H), 6.56 (s , 2 H), 6.29 (d, / = 8.4 Hz, 1H), 5.22-5.55 (m, 2H), 4.48 (d, / = 8.0 Hz, 1H), 4.21 - 4.29 (m, 3H), 2.64 (s, 3H), 1.31 (s, 3H). * H NMR (400 MHz, DMSO-d; + D 2 O) 5 8.66 (s, 1 H), 8.380 (s, 1 H), 7.77 (d / = 3.2 Hz 1H), 7 , 63 (d, / = 8.8 Hz, 1 H), 6.97-6.99 (m, 2 H), 6.78 (d, / = 3.2 Hz, 1 H), 6.29 (d / = 7.6 Hz, 1 H), 4.49 (d, / = 8.0 Hz, 1 H), 4.14-4.27 (m, 3 H), 2.65 (s, 3H), 1.32 (s, 3H).
[0373] [0373] To a solution of 7 - [[[3aR, 4R, 6R, 6aR) -6- (4-chloropyrrolo [2,3-d] pyrimidin-7-yl) -2,2,3a-trimethyl -6 , 6a-dihydro-4H-hole [3,4-d] [1,3] dioxol-4-yl] methoxy] quinoline (53b) (80.0 mg, 0.17 mmol) in THF (5.0 mL ) Tetrakis (triphenylphosphine) palladium (19.8 mg, 0.02 mmol), dimethylzinc (1.71 mL, 1.71 mmol) was added. The reaction mixture was stirred at 80 ° C for 4 h under N2 LCMS showed that the reaction was complete. The reaction mixture was poured into aqueous NHa4Cl (20.0 ml) and extracted with EA (30.0 ml x 3), dried over Na7SO4, filtered, concentrated in vacuo to give the crude product which was purified by column chromatography. silica gel (EP: EA = 10: 1) to provide 7 - [[[3aR, 4R, 6R, 6aR) -2,2,3a-trimethyl-6- (4-methylpyrrole [2,3-d] pyrimidin-7-yl) -6,6a-dihydro-4H-bore [3,4-d] [1,3] dioxol-4-yl] methoxy] quinoline (54a) (72.0 mg, 0.15 mmol , 88.5% yield) as a solid. LCMS [M + H]: 447.2 Step 2. Preparation of (2R, 3S, 4R, 5R) -3-methyl-5- (4-methylpyrrolo [2,3-d] pyrimidin-7-yl) -2 - (7-quinolyloxymethyl) tetrahydrofuran-3,4-diol (54)
[0374] [0374] A mixture of 7 - [[[3aR, 4R, 6R, 6aR) -2,2,3a-trimethyl-6- (4-methylpyrrolo [2,3-d] pyrimidin-7-yl) -6, 6a-dihydro -4H-bore [3,4-d] [1,3] dioxol-4-yl] methoxy] quinoline (54a) (72.0 mg, 0.15 mmol), water (0, 60 mL) and TFA (0.38 mL) at 40ºC for 2 h. LCMS showed that the reaction was completed. The reaction mixture was purified by prep-HPLC, eluted with MeCN in H2O (0.1% NH3-H2O) from 10.0% to 95.0% to give (2R, 3S, 4R, 5R ) -3- methyl-5 - (4-methylpyrrolo [2,3-d] pyrimidin-7-yl) -2- (7-quinolyloxymethyl) tetrahydrofuran-3,4-diol (Ex. 54) (26.0 mg , 0.06 mmol, 42.1% yield) as a white solid. LCMS [M + H]: 407.2 * H NMR (400 MHz, DMSO-ds, 5 8.83-8.84 (d, |) = 2.4 Hz, 1 H), 8.67 (s, 1 H), 8.30 (d, / = 8 Hz, 1 H), 7.92 (d, / = 9.2 Hz, 1 H), 7.83 (d,
[0375] [0375] To a solution of TEA (0.46 mL, 3.29 mmol) and Tosil chloride (417.88 mg, 2.19 mmol) in DCM (7.0 mL) was added [(3aR, 4R, 6R, 6aR) - 2,2,3a-trimethyl-6 - (4-methylpyrrolo [2,3-d] pyrimidin-7-yl) -6,6-dihydro-4H-hole [3,4-d] [ 1.3] dioxol-4-yl] methanol (10a) (350.0 mg, 1.10 mmol) and DMAP (66.9 mg, 0.55 mmol). The reaction mixture was stirred at 40 ° C for 1 h. ATLC (EA: PE = 1: 1, Re
[0376] [0376] To a solution of [(3aR, 4R, 6R, 6aR) -2,2,3a-trimethyl-6- (4-methylpyrrolo [2,3-d] pyrimidin-7-yl) 4-methylbenzenesulfonate - 6.6a-dihydro-4H-hole [3,4-d] [1,3] dioxol-4-yl] methyl (55a) (175.0 mg, 0.37 mmol) in DMF (2.0 mL) Cs2CO; 3 was added (361.2 mg, 1.11 mmol) and 2-bromo-3-chloro-quinolin-7-o] 1 (Int-9) (95.5 mg, 0.37 mmol). The reaction mixture was stirred at 80 for 16 h under N2 LCMS showed that the reaction was complete. The reaction mixture was concentrated in vacuo and diluted with EtOAc (10.0 ml). The mixture was washed with brine (10.0 mL X 2), dried over NazS Ou, filtered and concentrated in vacuo to give the crude product which was purified by silica gel column chromatography (EA: PE = 1: 1 ) to provide 7 - [[[3aR, 4R, 6R, 6aR) -2,2,3a-trimethyl -6- (4-methylpyrrolo [2,3-d] pyrimidin-7-yl) -6,6a-dihydro -4H- hole [3,4-d] [1,3] dioxol-4-yl] methoxy] -3-bromo-2-chloro-quinoline (55b) (75.0 mg, 0.10 mmol, 27, 2% yield) as a white solid. LCMS [M + H] J: 559.1
[0377] [0377] A solution of 7 - [[[3aR, 4R, 6R, 6aR) -2,2,3a-trimethyl -6- (4-methylpyrrolo [2,3-d] pyrimidin-7-yl) -6, 6a-dihydro-4H-bore [3,4-d] [1,3] dioxol-4-yl] methoxy] -3-bromo-2-chloro-quinoline (55b) (95.0 mg, 0.17 mmol ) in 1,4-dioxane (1.0 mL) and ammonium hydroxide (2.8 mL, 73.26 mmol) was stirred at 140ºC for 68 h in a sealed tube. LCMS showed that the reaction was carried out and 26.0% of SM was left. The reaction mixture was concentrated in vacuo to give the crude product 7 - [[[3aR, 4R, 6R, 6aR) -2,2,3a-trimethyl-6- (4-methylpyrrolo [2,3-d] pyrimidin-7 -yl) -6,6a-dihydro-4H-bore [3,4-d] [1,3] dioxol-4-yl] methoxy] -3-bromo-quinolin-2-amine (55c) (110.0 mg) as a yellow solid that was used directly in the next step. LCMS [M + H]: 540.1 Step 4. Preparation of (2R, 3S, 4R, 5R) -2 - [(2-amino-3-bromo-7 - quinolyl) oxymethyl] -3-methyl-5- (4-methylpyrrolo [2,3-d] pyrimidin-7-yl) tetrahydrofuran-3,4-diol (55)
[0378] [0378] A solution of 7 - [[[3aR, 4R, 6R, 6aR) -2,2,3a-trimethyl-6- (4-methylpyrrolo [2,3-d] pyrimidin-7-yl) -6, 6a-dihydro -4H-bore [3,4-d] [1,3] dioxol-4-yl] methoxy] -3-bromo-quinolin-2-amine (110.0 mg, 0.20 mmol) in water (1.0 ml) and TFA (1.5 ml, 20.19 mmol) was stirred at 40 ° C for 2 h. LCMS showed that the reaction was completed. The reaction mixture was purified by prep-HPLC, eluted with MeCN in H2O (0.1% NH3-H2O) from 10.0% to 95.0% to give (2R, 35, 4R, 5R ) -2 - [(2-amino-3-bromo-7-quinolyl) oxymethyl] -3-methyl-5- (4-methylpyrrolo [2,3-d] pyrimidin-7-yl) tetrahydrofuran-3,4- diol (Ex. 55) (11.1 mg, 0.02 mmol, 10.8% yield) as a white solid. LCMS [M + H]: 500.1 * H NMR (400 MHz, DMSO-d 5) 5 8.66 (s, 1 H), 8.29 (s, 1 H), 7.79 (d, / = 3.6 Hz 1 H), 7.60 (d, / = 8.4 Hz, 1 H), 6.94-6.98 (m, 2 H), 6.77 (d, / = 3.2 Hz , 1 H), 6.56 (s, 2H), 6.29 (d, / =
[0379] [0379] Example 56, an off-white solid, was prepared with a similar synthesis of Ex. 26, except for the replacement of 4-chlorobenzenemagnesium bromide by Int-8 in step 3. 'H NMR (500 MHz, Methanol-d 4) 8.11 (s, 1H), 7.40 (s, 1H), 7.30 (m, 2H), 7.27 (d, | = 3.7 Hz, 1H), 6.60 (d, | = 3.6 Hz, 1H), 5.85 (d, |) = 7.9 Hz, 1H), 5.01 (d, | = 3.6 Hz, 1H), 4.67 (d, |) = 7.9 Hz, 1H), 4.37 (d, |) = 3.7 Hz, 1H), 2.36 (s, 3H), 1.17 (s, 3H). LCMS (M + H *): 404.96 / 406.9.
[0380] [0380] A 4 mL vial with septum containing (R) - [(3aR, 4R, 6R, 6aR) -6- (4-chloropyrrolo [2,3-d] pyrimidin-7-yl) -2,2, 3a-trimethyl-6,6a-dihydro-4H-bore [3,4-d] [1,3] dioxol-4-i1] - (4-chloro-3-methyl-phenyl) methanol (57a) (64. mg, 0.14 mmol) and palladium; triphenylphosphane (8.02 mg, 0.01 mmol) under nitrogen was charged with THF (1 mL) and purged with nitrogen for 10 min. The flask was then loaded with dimethylzinc (0.3 mL, 0.61 mmol) and heated to 70ºC for 3 h. Complete by LCMS. The reaction mixture was terminated by dropwise addition of NaHCO solution; 3 sat. (5 drops) at room temperature under a nitrogen atmosphere with vigorous stirring. The reaction mixture was diluted with water and extracted with EtOAc three times. The organic layers were combined, washed with brine, dried over Na, SO, and filtered. The filtrate was concentrated under reduced pressure and purified on a silica gel column chromatography of 12 g using hexane / EtOAc (0 - 85%, wet loaded in DCM) to produce (R) - [(3aR, 4R, 6R, 6aR) - 2,2,3a-trimethyl-6- (4-methylpyrrolo [2,3-d] pyrimidin-7-yl) -6,6a-dihydro-4H-bore [3,4-d] [1, 3] dioxol -4-yl] - (4-chloro-3-methyl-phenyl) methanol (57b) (27 mg, 0.0608 mmol, 44.1% yield) as a white solid. LCMS M + H * Found: 443.69 / 444.01, * H NMR (500 MHz, CHLOROPHORMUM-d 3) 5 8.81 (s, 1H), 7.28 (m, 2H), 7.16 ( d, | = 8.2 Hz, 1H), 6.22 (m, 1H), 4.78 (t | = 10.8 Hz, 1H), 4.65 (m, 1H), 4.18 (d , | = 8.3 Hz, 1H), 2.94 (s, 1H), 2.36 (s, 3H), 1.83 (s, 3H), 1.68 (s, 3H), 1.51 (s, 3H), 1.42 (s, 3H).
[0381] [0381] For (R) - [(3aR, 4R, 6R, 6aR) -2,2,3a-trimethyl-6- (4-methylpyrrolo [2,3-d] pyrimidin-7-yl) -6,6a -dihydro -4H-bore [3,4-d] [1,3] dioxol-4-i1] - (4-chloro-3-methyl-phenyl) methanol (57b) (27mg, 0.06 mmol) in methanol (1 mL) a few drops of conc. at 0 ºC. The reaction was stirred at room temperature.
[0382] [0382] Example 58, an off-white solid, was prepared with a similar synthesis of Ex. 57, except replacing 57a with 37b in step 1. * H NMR (500 MHz, Methanol-d4) 5 8.65 (s, 1H), 7.67 (d, J = 3.8 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.43 (d, |) = 8.4 Hz, 1H ), 7.37 (dd, |) = 2.0, 8.4 Hz, 1H), 6.75 (d) = 3.7 Hz, 1H), 6.07 (d, | = 7.9 Hz , 1H), 4.98 (d, | = 5.0 Hz, 1H), 4.69 (d, | = 7.9 Hz, 1H), 4.29 (d, |) = 5.0 Hz, 1H), 2.73 (s, 3H), 1.27 (s, 3H).
[0383] [0383] To a solution of (2-bromo-5-chloro-phenyl) methoxy-tert-butyl-dimethyl-silane (8.46 9, 25.2 mmol) in dry THF (208 mL) was added n-BuLi (12.6 mL, 20.2 mmol) at -78 ° C and stirred for 5 min under N 2. 26b (4.0 g, 10.1 mmol) in dry THF (10 mL) was added and stirred at - 78ºC for 5 min. TLC (PE: EA = 3: 1, Rk; = 0.5) showed that the reaction was complete. The reaction mixture was poured into aqueous NH 4 CI and extracted with EA (300 ml x 3), and the solvent was concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography (PE: EA = 5 : 1) to give 64a (3.09 g, 5.11 mmol, 50.7% yield) as a white solid. LCMS [IM + H]: 592.2;
[0384] [0384] To a solution of 64a (3.0 9, 5.1 mmol) in toluene (30 mL) DIBAL-H was added (9.5 mL, 15.2 mmol) at -78 ° C and stirred for 1 h under N.>. TLC (PE: EA = 5: 1, R $ = 0.4) showed that the reaction was complete. The reaction mixture was poured into aqueous NHaCl (300 ml) and extracted with EA (300 ml x 3) The solvent was concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography (PE: EA = 5 : 1) to give 64b (2.50 9, 4.12 mmol, 81.39% yield) as a white solid. LCMS [M + H]: 594.2 Step 3. Preparation of O - [(R) - [(3aR, 4R, 6R, 6aR) -6- (4-chloropyrrolo [2,3-d] pyrimidine-) methylsulfanylmethanothioate 7-yl) -2,2,3a-trimethyl -6,6a-dihydro-4H-bore [3,4-d] [1,3] dioxol-4-yl] - [2 - [[tert-butyl ( dimethyl) silyl] oxymethyl] -4-chloro-phenyl] methyl] (64c)
[0385] [0385] To a solution of 64b (400 mg, 0.67 mmol) in THF (10 mL) was added NaH (48.4 mg, 1.21 mmol) and stirred at 0 ° C for 0.5 h. CS 2 (153.7 mg, 2.0 mmol) was added and stirred at 0 ° C for 0.5 h, then CH3l (191 mg, 1.35 mmol) was added and stirred at room temperature for 1 h. TLC (PE: EA = 3: 1, Rf = 0.7) showed that the reaction was complete. The reaction mixture was poured into NH, aqueous CI (50 ml) and extracted with EA (300 ml x 3). The solvent was concentrated under reduced pressure to give a crude product which was purified by silica gel column chromatography (PE: EA = 20: 1) to give 64c (267 mg, 0.38 mmol, 57% yield) as a white solid. * H NMR (400 MHz, DMSO-d6) 5 8.93 (s, 1 H), 8.14 (d, / = 3.6 Hz, 1 H), 7.52-7.65 (m, 3 H), 6.99 (d, / = 3.6 Hz, 1 H), 6.43-6.47 (m, 2 H), 5.30 (s, 1 H), 5.15 (d / = 14.8 Hz, 1H),
[0386] [0386] To a solution of 64c (430 mg, 0.63 mmol) and AIBN (103 mg, 0.63 mmol) in toluene (20 mL) was added tributibutylin (183 mg, 0.63 mmol) under N, 7 , and the reaction mixture was stirred at 115 ° C for 18 h under No. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE: EA = 20: 1) to give 64d (260 mg, 0.44 mmol, 70% yield) as a solid. LCMS [M + H] J: 576.2 Step 5. Preparation of [2 - [[[3aR, 4R, 6R, 6aR) -2,2,3a-trimethyl-6- (4-methylpyrrole [2,3- d] pyrimidin-7-yl) -6,6a- dihydro -4H-bore [3,4-d] [1,3] dioxol-4-yl] methyl] -5-chloro-phenyl] methoxy-tert-butyl -dimethylsilane (64e)
[0387] [0387] To a solution of 64d (150 mg, 0.26 mmol) and Tetrakis (triphenylphosphine) palladium (30 mg, 0.03 mmol) in THF (10 mL) was added dimethylzinc (2.6 mL, 2.59 mmol), the reaction mixture was stirred at 80 ° C for 3 h. LCMS showed that the reaction was complete. The reaction was poured into NH, CI (50 ml) aqueous and extracted with EA (50 ml x 3). The solvent was concentrated under reduced pressure to give a crude product which was purified by combined reverse phase flash (neutral condition) to give 64e (110 mg, 0.19 mmol, 74.5% yield) as a white solid. LCMS [M + H]: 558.2 Step 4. Preparation of (2R, 35, 4R, 5R) -2 - [[4-chloro-2- (hydroxymethyl) phenyl] methyl] -3-methyl-5- ( 4-methylpyrrolo [2,3-d] pyrimidin-7-yl) tetrahydrofuran-3,4-diol (64)
[0388] [0388] A solution of 64e (110 mg, 0.19 mmol) in water (3 mL) and TFA (2 mL, 27 mmol) was stirred at 40 ° C for 1 h. LCMS showed that the reaction was complete. The solvent was concentrated under reduced pressure and purified by preparative HPLC (0.1% NH3.H20O), eluted with H20: CH3CN from 90: 10 to 5: 95 to give 64 (41 mg, 0.10 mmol, 51% yield) as a white solid. LCMS [M + HJ]: 404.1 * H NMR (400 MHz, DMSO-d6) ô 8.64 (s, 1 H), 7.90 (d / = 3.6 Hz, 1 H), 7, 33 (s, 1 H), 7.10 (d, / = 1.2 Hz, 2 H), 6.80 (d, / = 3.6 Hz, 1 H), 6.10 (d, J = 7.6 Hz, 1 H), 5.40 (d, / = 6.8 Hz, 1 H), 5.21 (t / = 5.6 Hz, 1 H), 4.96 (s, 1 H ), 4.44-4.57 (m, 3 H), 4.01-4.05 (m, 1 H), 2.89-2.91 (m, 2 H), 2.66 (s, 3 H), 1.33 (s, 3H). * H NMR (400 MHz, DMSO-d6 + D 2 O) 5 8.64 (s, 1 H), 7.87 (d, /) = 3.6 Hz, 1 H), 7.33 (s, 1H), 7.11 (d, / = 1.6 Hz, 2 H), 6.81 (d, / = 7.6 Hz, 1 H), 6.10 (d, J = 7.6 Hz, 1 H), 4.45-4.56 (m, 3 H), 4.04 (d, / = 6.4 Hz, 1 H), 2.89 (d, / = 6.8 Hz, 2 H ), 2.67 (s, 3H), 1.34 (s, 3H).
[0389] [0389] 37b (18 mg, 0.04 mmol) was added to a solution of triphenylphosphine (23.89 mg, 0.09 mmol), diisopropyl azodicarboxylate (0.01 mL, 0.07 mmol) and 4- acid nitrobenzoic acid (9.3 mg, 0.06 mmol) in THF (1 mL) at 0ºC. The resulting solution was stirred at room temperature for 2 h and then heated to 60 ° C for 20 h. The mixture was diluted with water and EtOAc, the organic phases were separated, washed with water, brine and dried over NasSO. The solvent was evaporated in vacuo, and the residue was purified by flash column chromatography (0-50% EtOAc in hexane) to give 66a (20 mg, 0.032 mmol, 85% yield). LCMS [M + H]: 633.9 Step 2. Preparation of (R) - [(3aR, 6R, 6aR) -6- (4-aminopyrrolo [2,3-d] pyrimidin-7-yl) -2, 2,3a-trimethyl-6,6a-dihydro-4H-hole [3,4-d] [1,3] dioxol-4-i1] - (3,4-dichlorophenyl) methane! (66b)
[0390] [0390] 66a (22 mg, 0.03 mmol) and ammonium hydroxide (0.26 mL, 6.85 mmol) and 1,4-dioxane (1 mL) were placed in a sealable tube. The reaction was heated to 120 ° C overnight, cooled to room temperature and the solvent was evaporated in vacuo to give crude 66b (19 mg, 0.041 mmol, 119% yield) which was used in the next step without further purification. LCMS [M + H]: 464.9 Step 3. Preparation of (2R, 3S, 4R, 5R) -5- (4-amino-7H-pyrrolo [2,3-dj pyrimidin-7-yl) -2- ((S) - (3,4-dichlorophenyl)) (hydroxy) methyl) -3-methyltetrahydrofuran-3,4-diol (66)
[0391] [0391] In a 66b flask (20 mg, 0.04 mmol) was placed in THF (1 mL) followed by 4N HCl (0.11 mL, 0.44 mmol) and the reaction was stirred overnight. More 4N HCI (0.11 mL, 0.44 mmol) was added and the reaction was stirred overnight. LCMS shows that the reaction was complete. Saturated aqueous NaHCO3 was added until the solution was slightly basic. The mixture was extracted with DCM (3 ml), the organic phases were washed with brine and dried over MgSO4. The solvent was evaporated in vacuo, and the residue was purified by flash column chromatography (0 - 40% EtOAc / hexanes) to provide 66 (7.2 mg, 0.017 mmol, 40% yield). LCMS [M + HJ]: 424.9 1H NMR (500 MHz, DMSO-d6) 5 8.08 (s, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.53 - 7.43 (m, 2H), 7.36 - 7.23 (m, 2H), 7.14 (s, 2H), 6.59 (d, | = 3.6 Hz, 1H), 5.79 (d, | = 8.1 Hz, 1H), 528 (d J) = 7.1 Hz, 1H), 4.80 (d, | = 8.6 Hz, 1H), 4.77 (s, 1H ), 4.47 (t |) = 7.6 Hz, 1H), 3.98 (d, J = 1.3 Hz, 1H), 1.45 (s, 3H).
[0392] [0392] To a mixture of 19a (350 mg, 1.03 mmol) and Pd (PPh3) to (119 mg, 0.10 mmol) in THF (10 mL) was added dimethylzinc (983.2 mg, 10.30 mmol) dropwise under N2 atmosphere. The reaction was stirred at 80ºC for 3 hours. TLC (PE: EA = 10: 1) showed that the reaction was complete. The mixture was poured into NH, aqueous 4Cl (30 ml) and extracted with EA (30 ml X 3). The organic phases were combined, dried over Na7SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA = 50: 1 to 5: 1) to give 67a (300 mg, 0.81 mmol, 78% yield) as a white solid. LCMS: [M + H]: 320.2.
[0393] [0393] For a solution of 67a (300 mg, 0.94 mmol), TEA (0.39 mL, 2.82 mmol) and DMAP (57 4 mg, 0.47 mmol) in DCM (20 mL) was added tosyl chloride (358 mg, 1.88 mmol) and the reaction mixture was stirred at 40 ° C for 16 h. TLC (PE: EA = 1: 1, R $ = 0.4) showed that the reaction was complete. The mixture was poured into H, O / DCM washed with H, O and brine, purified by chromatography on silica gel (PE: EA = 10: 1 to 2: 1) to provide (67b) (220 mg, 0.4 4 mmol, 46.5% yield) as a white solid. LCMS: [M + H]: 474.1.
[0394] [0394] To a solution of 67b (60 mg, 0.13 mmol) in DMF (2 mL), 67c (prepared according to WO 2018/065365; 18.8 mg, 0.13 mmol) was added and Cs2CO; 3 (124 mg, 0.38 mmol) and the reaction mixture was stirred at 80 ° C for 16 h under No. atmosphere. LCMS showed that the reaction was complete. The reaction was concentrated to dryness and the residue was taken up in EtOAc (10 ml) and the organic layer was washed with water (2 x 10 ml) and then with saturated brine solution (1 x 20 ml). The organic layers were separated, dried under (MgSO4) and concentrated to give (67d) (60 mg, 0.11 mmol, 89.5% yield). LCMS: [M + H]: 450.4.
[0395] [0395] To a solution of 67d (100 mg, 0.18 mmol) in water (3 mL) was added 2,2,2-trifluoroacetic acid; TFA (3.43 mL, 44.5 mmol), and the mixture was stirred at 25 ° C for 90 min. LCMS showed that the reaction was complete. The residue was purified by means of prep-HPLC, eluted with CH3CN in H2O (0.1% NH.OH) from 5% to 95% to give (2R, 35, 4R, 5R) -3- methyl-2- [(3-methylimidazo [1,2-a] pyridin-7-yl) oxymethyl] -5- (4-methylpyrrolo [2,3-d] pyrimidin-7-yl) tetrahydrofuran-3,4- diol (27 mg, 0.06 mmol, 37% yield) as a light yellow solid. LCMS: [M + H]: 410.2.
[0396] [0396] * HNMR (400 MHz, DMSO-d6 + D> O): 58.66 (s, 1 H), 8.25- 8.27 (m, 1 H), 7.77-7.78 ( m, 1 H), 7.33-7.34 (m, 1 H), 7.08-7.09 (m, 1 H), 6.89-6.91 (m, 1 H), 6, 77-6.78 (m, 1 H), 6.27-6.29 (m, 1 H), 4.48-4.50 (m, 1H), 4.27-4.29 (m, 2H ), 4.22-4.24 (m, 1H), 2.65 (s, 3H), 2.43 (s, 3H), 1.32 (s, 3H).
[0397] [0397] The examples listed below have been prepared or can be prepared using methods analogous to those described above.
[0398] [0398] The compounds were solubilized and diluted 3 times in 100% DMSO. These diluted compounds were further diluted in the assay buffer (50 mM Tris-HCl, pH 8.5, 50 MM NaCl, MgCl; 5 mM, 0.01% Brij35, 1 mM DTT, 1% DMSO) to 10 at the dose in ICsº mode at a concentration 10 times higher than the desired test concentration. Standard reactions were performed in a total volume of 50 µl in assay buffer, with histone H2A (5 µM final) as a substrate. To this was added the diluted PRMT5 / MEP50 complex to provide a final assay concentration of 5 nM and the compounds were left to pre-incubate for 15 to 20 minutes at room temperature. The reaction was initiated by adding S- [3H-methyl] -adenosyl-L-methionine (PerkinElmer) to the final concentration of 1 µM. After a 60-minute incubation at 30ºC, the reaction was stopped by adding 100 mL of 20% TCA. Each reaction was identified on the filter plate (MultiSscreen FB filter plate, Millipore) and washed 5 times with PBS buffer, scintillation fluid was added to the filter plate and read in a scintillation counter. The IC5o9 values were determined by adjusting the data to the standard parameters of 4 with Hill Slope using the GraphP ad Prism software.
[0399] [0399] Screening of initial compounds in A549 cells: The compounds were dissolved in DMSO to produce 10 mM of stock and subsequently diluted to 0.1 and 1 mM. A549 cells were maintained in PRM! 1640 (Corning Cellgro, Catalog No. 10-040-CV) supplemented with 10% v / v FBS (GE Healthcare, Catalog No. SH30910.03). The day before the experiment, 1.25 x 10 cells were seeded in a 6-well plate in 3 ml of medium and incubated overnight. The next day, the medium was changed and 3 µl of compound solution was added (dilution 1: 1,000, final concentration of 0.1 and 1 µM; DMSO concentration: 0.1%) and incubated for 3 days. The cells incubated with DMSO were used as a vehicle control. The cells were washed once with PBS, trypsinized in 150 µL of 0.25% trypsin (Corning, Catalog No.: 25-053-CI), neutralized with 1 ml of complete medium, transferred to micr º and centrifuge tubes collected. The cell pellet was then resuspended in 15 µl PBS, lysed in 4% SDS and homogenized through the homogenizer column (Omega Biotek, catalog number: HCRO003). Total protein concentrations were determined by the BCA assay (ThermorFisher Scientific, Catalog #: 23225). Lysates were mixed with 5 x Laemmli buffer and boiled for 5 min. Forty ug of total protein were separated into SDS-PAGE gels (Bio-Rad, catalog number: 4568083, 4568043), transferred to the PVDF membrane, blºCked with 5% dry milk (Bio-Rad, catalog number: 1706404 ) in TBS with 0.1% Tween 20 v / v (TBST) for 1 hour at room temperature (RT) and incubated with primary antibodies (SDMA: Cell signaling, Catalog number: 13222, 1: 3,000; H3R8me2s: E pigentek, Catalog number: A-3706-100, 1: 2,000; B-actin: Abcam, Catalog number: ab8227, 1:
[0400] [0400] To determine enzyme inhibition IC 50 values using Western Blot analysis, cells were seeded at high density of 5 x 5 cells / ml in 3 ml of medium (PRMI + 10% v / v FBS). Serial dilutions of nine points in three parts of the compound were added to the cells (3 µl, dilution 1: 1,000, the concentration of DMSO was 0.1%; the maximum final concentration was 10 or 1 µM, depending on the potency of the compounds) and incubated for 3 days. The cells incubated with DMSO were used as a vehicle control. The cells were collected and subjected to western blot analysis as described above. The SMD3me2s and H3R8me2s bands were quantified by Image).
[0401] [0401] Granta-519 cells were maintained on PRMI 1640 (Corning Cellgro, Catalog No. 10-040-CV) supplemented with 10% v / v FBS (GE Healthcare, Catalog No. 5SH30910.03).
[0402] [0402] On the day of the experiment, compound working stocks were further diluted 1:50 with fresh medium in a 96-well plate, and 10 µl of diluted drugs were added to a new 96-well plate for the proliferation assay . The cells that grow in the exponential phase were centrifuged at 1500 rpm for 4 min and resuspended in fresh medium to reach a density of 0.5 x 10 E cells / ml. 200 µl of cells were added to a 96-well plate containing diluted drugs and incubated for 3 days. DMSO was used as a carrier control.
[0403] [0403] One day 3.10L of Kit-8 cell counting solution (CCK-8, J ojindo, CK04-13) was added to a new 96-well plate. The cells incubated with drugs for 3 days were resuspended by pipetting up and down, and 100 µL of cells were transferred to a 96 well plate containing CCK-8 reagent to measure viable cells. The plates were incubated in the CO2 incubator for 2 hours and the OD450 values were measured with a micro cavity reader (iMark microplate reader, Bio-Rad).
[0404] [0404] For re-plating, the compound working stocks were diluted 1:50 with fresh medium and 10 ul of diluted medications were added to a new 96-well plate. Cells from the day 3 plate (50 µl) were added to a 96 well plate containing fresh drug and 150 µl of fresh medium was added to reach 200 µl in volume. The plate was returned to the CO 2 incubator and incubated for another 3 days. Measurement and re-plating of viable cells were repeated on day 6 and the final measurement of viable cells was performed on day 10.
[0405] [0405] The percentage of viable cells, in relation to the DMSO transporter control, were calculated and plotted in Graphpad Prism ([Inhibitor] as a function of the normalized response - variable slope) to determine the CI values, of proliferation on the day 10.
[0406] [0406] The Examples in Table A (above) will have an ICs9 value in the PRMT5 assay of less than 200uM. The biological activity for exemplary compounds of the disclosure is reported in Table C.
[0407] [0407] The compounds were first dispersed in freshly prepared FaSSIF buffer (http://biorelevant.com/site media / upload / documents / How to make FaSSIF FeSS IF and FaSSGF.pdf) at 1 mg / mL, respectively, and the Standard samples were prepared by preparing 1 mg / mL of test compounds in the DMSO. The compounds were then sufficiently mixed by a vortex mixer for 30 seconds and stirred at 25ºC using 300 rpm for 4 hours in a thermomixer. After incubation, the prepared samples were centrifuged at 10,000 rpm for 10 min to remove the undissolved solid, the resulting supernatants were applied to the HPLC. The actual concentrations of the compounds were assessed by measuring the peak area, and the solubility (S) of the compounds was calculated according to the following equation: S = Csmp = C sta * (A smp / Asta) * (V sta / V smp ) Where C is the sample concentration in ug / mL, A is the peak area and V is the injection volume.
[0408] [0408] In a PK study without crossbreeding (SD, male, without fasting) in mice, Example 47 was dosed at 1 mg / kg (DMA: 20% HPBCD = 5: 95, solution) via iv administration (N = 3) and 1 mg / kg (0.5% Na CMC + 0.5% Tween80, solution) via oral meter (po) (N = 3). He showed a mean T 12 of 4.1 hours, Vss of 3.1 L / kg, blood clearance of 8.8 mL / min / kg in the i.v .; showed normalized dose AUC of 3246 ng * h * kg / mL / mg and> 100% oral bioavailability in the p.o.
[0409] [0409] Granta-519 cells were maintained in DMEM medium supplemented with 10% fetal bovine serum and 2 mM L-glutamine, at 37ºC in a 5% CO atmosphere, in the air. Exponentially growing cells were harvested and 1x10 cells in 0.1 mL of PBS with Matrigel (1: 1) were injected subcutaneously into the region of the right lower flank of each mouse for tumor development. Treatments were started when the average tumor size reached approximately 300-400mm . The mice were divided into groups using StudyDirector "" M software (Studylog Systems, Inc. CA, USA) and an optimal randomization design (generated by the Matched distribution or the Stratified method) that shows minimal variation from group to group in the volume of the tumor was selected for group allocation. Example 47 or carrier (Na 0.5% CMC + 0.5% Tween80, suspension)
[0410] [0410] To measure the levels of SDMA in the tumor samples, the tumors of each mouse were weighed and homogenized in RIPA buffer supplemented with protease inhibitor (cOmplete '", Protease Inhibitor Cocktail without EDTA, Roche). The lysate was centrifuged at 14,000 rpm for 30 min at 4ºC to remove debris. Total protein concentrations of the lysate were determined by the BCA assay (ThermoFisher Scientific, Catalog #: 23225). An equal amount of total proteins from each tumor was separated on SDS gel - PAGE, and SDMA levels were determined by WB as previously described.
[0411] [0411] Following this protocol, Example 47 showed an average of 46% (N = 5) of tumor growth inhibition at 30 mg / kg with 1% body weight loss; an average of 79% inhibition of tumor growth at 50 mg / kg with 8% body weight loss. It also showed> 90% inhibition of sSDMA at 30 mg / kg and no detectable sSDMA at 50 mg / kg.
[0412] [0412] In addition, this disclosure addresses the following aspects:
1. A compound of Formula |:
Rô À, Ho e | the EnaR
OA o N o z Ri
H Rº | or a pharmaceutically acceptable salt or solvate thereof; where R * is -Co-Cealqu-C1-Cçealquila, -Co-Cçalqu-C1-Cehaloalkyl, -C1-Cealg-O- Ci-Cealquila, -Ci-Cçalqgu-S-Ci-Cçéalquila, —-Cr-Céçalqu -S-Ci-Céalqu-CO2H, -Cyr- Cçalqu-arila, -Cr-Cçalqu-O-arila, -Cr-Cçalqu-NH-arila, -Ci-Céçalqu-S-arila, -Co- Cçealqu-heteroarila, -C1-Cealqu-O-heteroaryl, -C1-Cçalqu-S-heteroaryl, -C1-Cealqu-NH-heteroaryl, or -C (O) NH-aryl; Rº is -CiCçalguila, y -Cr-Céhaloalkyl, -C> -Cçéalenenila, or —Cx- Cçealquinila; R is H, haologen, NH>, or -C1-Cecealkyl; Rº is halo, -Ci-Cealguila, -Ci-Céalqu-O - Ci-Cealguila, -NRÓRE, - NHCONR "RÔ ', -NHC (S) NRÓR 6', -NH-OR $, or -NH-NR º R º; R * is H, halo, -C7-Cálquila, -C-Céhalogenoalkyl, -C2-Cçéalquenila, -C> 2- Cçealquinila, or -c 1 .c 6 alkyl-OH; and Rº and RÔ are each one, independently, H, Ci-Cçéalkyl, or Cr Cçealqu-O-C1-Cçalquila, or Rº and Rº, together with the atom to which they are attached, form a heterocycloalkyl C2-Cç ring.
2. The compound according to aspect 1, wherein R * is -C1-Cecéalkyl- O-heteroaryl.
3. The compound according to aspect 2, in which the -C; -Cçéalk-O-heteroaryl is ((2-amino-3-bromoquinolin-7-yl) oxy) methyl, (((2-amino- 3-chloroquinolin-7-yl) oxy) methyl, ((2-amino-3-fluoroquinolin-7-yl) oxy) methyl, ((2 - ((cyclopropylmethyl) amino) quinolin-7-yl) oxy) methyl, ((2- (methylamino)) quinolin-7-yl) oxy) methyl, ((2-aminoquinolin-7-yl) oxy) methyl, ((indol-6-yl) oxy) methyl or (((indazol-6 -yl) oxy) methyl).
4. The compound according to aspect 1, wherein R1 is -C1-Cçalg-S- heteroaryl.
5. The compound according to aspect 4, wherein the -C1-Ceéalk-S-heteroaryl is ((2-amino-3-bromoquinolin-7-yl) thio) methyl, ((2-amino-3- chloroquinolin-7-yl) thio) methyl, ((2-amino-3-fluoroquinolin-7-yl) thio) methyl, ((2 - ((cyclopropylmethyl) amino) quinolin-7-yl) thio) methyl, (( 2- (methylamino) quinolin-7-yl) thio) methyl, (((2-aminoquinolin-7-yl) thio) methyl, ((indol-6-yl) thio) methyl, (2- (methoxyamino) quinolin-7 - yl) thio) methyl, ((quinolin-7-yl) thio) methyl, ((3-methylimidazo [1,2-a] pyridin-7-yl) thio) methyl or ((indazol-6-yl) thio ) methyl.
6. The compound according to aspect 1, wherein R1 is -C1-Cçéalk-NH-heteroaryl.
7. The compound according to aspect 6, wherein the -C; -Cçalqu-NH-heteroaryl is ((2-amino-3-bromoquinolin-7-yl) amino) methyl, ((2-amino-3 - chloroquinolin-7-yl) amino) methyl, ((2-amino-3-fluoroquinolin-7-yl) amino) methyl, ((2- ((cyclopropylmethyl) amino) quinolin-7-yl) amino) methyl, ( (2- (methylamino) quinolin-7-yl) amino) methyl, ((2-aminoquinolin-7-yl) amino) methyl, ((indol-6-yl) amino) methyl, (2- (methoxyamino) quinolin- 7-yl) amino) methyl, ((quinolin-7-yl) amino) methyl, ((3-methylimidazo [1,2-a] pyridin-7-yl) amino) methyl or ((indazol-6-yl) amino) methyl.
8. The compound according to aspect 1, wherein R1 is -Co-Csalqu-heteroaryl.
9. The compound according to aspect 8, in which the -Co-Cçealqu-heteroaryl is 2- (2-amino-3-bromoquinolin-7-yl) ethyl, 2- (2-amino-3-chloroquinolin- 7-yl) ethyl, 2- (2-amino-3-fluoroquinolin-7-yl) ethyl, 2- (2 - ((cyclopropylmethyl) amino) quinolin-7-yl) ethyl, 2- (2- (methylamino) quinolin-7-yl) ethyl, 2- (2-aminoquinolin-7-yl) ethyl, ((indol-6-yl) ethyl, or ((indazol-6-yl) ethyl).
10. The compound according to aspect 1, wherein R 'is -Cx-C-alkeal-S-alkyl.
11. The compound, according to aspect 10, in the -C1-Cçealqu-S-C1-Crealquila is -CH2-S-CH3.
12. The compound according to aspect 1, wherein R 'is --C1- Cçalg-S-C1-Cçalg-CO, H.
13. The compound, according to aspect 12, in the -C7-Cçalg-S-C1-Cealg-CO2H is CH7-S-CHCHCHINH2) -CO2H.
14. The compound according to aspect 1, wherein R 'is -Cx- Cealeal-O-C1-Calkyl.
15. The compound, according to aspect 14, in the -C1-Cealqu-O-C1-Crealquila is -CH2-0-CH3.
16. The compound according to aspect 1, wherein R '* is -Cr- Cçalqu-O-aryl.
17. The compound according to aspect 16 in which the C1-Cçalqu-O-aryl is -CH7-O-phenyl, -CH7-O-difluorophenyl, -CH2-0-3,4-difluorophenyl, -CH2- 0-4- chlorophenyl, -CH2-0-3-chloro-4-fluorophenyl, -CH2-0-4-chloro-3-fluorophenyl, -CH7-O-dichlorophenyl, -CH72-0-3,4-dichlorophenyl, -CH2-0-3-methyl-4-chlorophenyl, -CH2-0-3- fluoro-4-trifluoromethylphenyl, -CH2-0-3- (aminomethyl) phenyl, or -CH2-0-3- (urea) phenyl .
18. The compound according to aspect 1, wherein R * is -Co- Cealeal-C1-Cehaloalkyl.
19. The compound, according to aspect 18, in the -Co-Ccealqu-C1-Cehaloalkyl is -CH2-CI.
20. The compound according to aspect 1, wherein R '* is -Cx- Cçalqu-aryl.
21. The compound according to aspect 20, wherein -C1-Cçealq- aryl is -CH, -difluorophenyl, -CH2-3,4-difluorophenyl, -CH, 2-4-chlorophenyl, -CH, -3 - chloro-4-fluorophenyl, -CH2-4-chloro-3-fluorophenyl, -CH-dichlorophenyl, -CH2-3,4-dichlorophenyl, -CH>; -3-methyl-4-chlorophenyl, -CH2-3-fluoro-4-trifluoromethylphenyl, - CH (OH) -4-chlorophenyl, -CH (OH) -3,4-dichlorophenyl, -CH (OH) -3, 4-difluorophenyl, - CH (OH) -3-fluoro-4-chlorophenyl, -CH (OH) -3-chloro-4-fluorophenyl, -CH (OH) -3-methyl-4-chlorophenyl, -CH (OH ) -3-fluoro-4-trifluoromethylphenyl, -CH (F) -4-chlorophenyl, -CH (F) - 3,4-dichlorophenyl, -CH (F) -3,4-difluorophenyl, -CH (F) - 3-fluoro-4-chlorophenyl, -CH (F) - 3-chloro-4-fluorophenyl, - -CH (F) —-3-methyl-4-chlorophenylay - “- CH (F) -3-fluoro-4 - trifluoromethylphenyl, -CH (NH2) -4-chlorophenyl, -CH (NH2) -3,4-dichlorophenyl, -CH (NH> 2) - 3,4-difluorophenyl, -CH (NH2) -3-fluoro-4 -chlorophenyl, -CH (NH2) -3-chloro-4-fluorophenyl, -CH (NH2) -3-methyl-4-chlorophenyl, -CH (NH2) -3-fluoro-4-trifluoromethylphenyl, -CH (Me) - 4-chlorophenyl, -CH (Me) -3,4-dichlorophenyl, -CH (Me) -3,4-difluorophenyl, -CH (Me) -3-fluoro-4-chlorophenyl, -CH (Me) -3 -chloro-4-fluorophenyl -CH (Me) -3-methyl-4-chlorophenyl, -CH (Me) -3-fluoro-4-trifluoromethylphenyl, -C (Me) (OH) -4-chlorophenyl, -C ( Me) (OH ) -3,4-dichlorophenyl, -C (Me) (OH) -3,4 -difluorophenyl, -C (Me) (OH) -3- fluoro-4-chlorophenyl, -C (Me) (OH) -3 -chloro-4-fluorophenyl, -CH (Me) (OH) -3-methyl-4-chlorophenyl or -C (Me) (OH) -3-fluoro-4-trifluoromethylphenyl.
22. The compound, according to any of aspects 1 to 21, in which R is C1-Cçalquila, preferably methyl.
23. The compound, according to any of aspects 1 to 21, in which R is -C1-Céhaloalkyl, preferably -CF3.
24. The compound, according to any one of aspects 1 to 21, in which R is -C> -Cçéalkenyl, preferably vinyl.
25. The compound, according to any of aspects 1 to 21, in which R is -C> -Calquinyl, preferably ethynyl.
26. The compound, according to any one of aspects 1 to 25, in which R is H.
27. The compound of any one of aspects 1 to 26, where Rº is -Ci-Cçalquila.
28. The compound, according to any of aspects 1 to 26, where Rº is -C1-Cçealg-O-C1-Crealquila.
29. The compound, according to any of aspects 1 to 26, in which Rº is chlorine, fluorine, bromine, or iodine.
30. The compound, according to any of aspects 1 to 26, where Rº is -NRºRº, where R $ and Rº are both preferably H.
31. The compound, according to any one of aspects 1 to 26, where Rº is -NHCONR "R", where Rº and RÔ are both preferably - Cir-Crealquila.
32. The compound, according to any of aspects 1 to 26, where Rº is NHC (S) NRºRº.
33. The compound, according to any of aspects 1 to 26, in which Rº is -NH-O-R $, in which R $ is preferably -C1-Cçalquila.
34. The compound, according to any of aspects 1 to 26, in which Rº is -NH-NRºRÔ, in which R6 and Rº are both preferably -C1- Cçalguila or in which R $ is preferably -Ci-Cçalguila and Rº is preferably H.
35. The compound, according to any of aspects 1 to 34, in which D H.
36. The compound according to any one of aspects 1 to 34, wherein R * is halo, preferably fluorine.
37. The compound of any one of aspects 1 to 34, where R * is -Cr-Cçalquila.
38. The compound of any one of aspects 1 to 34, in which R is -Cr-Cehaloalkyl.
39. The compound according to any one of aspects 1 to 34, wherein R * is -C2-Cçéalkenyl, preferably vinyl.
40. The compound according to any one of aspects 1 to 34, wherein R * is -C> -Calquinyl, preferably ethynyl.
41. The compound according to any one of aspects 1 to 34, wherein D is c1.c6alg-OH.
42. A pharmaceutical composition comprising a compound defined according to any one of aspects 1 to 41, and a pharmaceutically acceptable excipient.
43. The method for inhibiting an arginine methyltransferase 5 (PRMTB5) enzyme, characterized by the fact that it comprises: contacting the PRMT5 enzyme with an effective amount of a compound defined according to any of aspects 1 to 41.
44. The method of treating a disease or disorder associated with aberrant PRMT5 activity in a subject that comprises administering to the subject, a compound defined according to any one of aspects 1 to 41.
45. The method according to aspect 44, in which the disease or disorder associated with aberrant PRMT5 activity is breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, cervical cancer, cervical cancer, leukemia, such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myeloid leukemia (AML), leukemia, chronic myeloid leukemia (AML), leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid cancer or hemoglobinopathies such as b-thalassemia and sickle cell disease (SCD).
46. A compound of Formula |: Rô o. SA sº vw
AA XL o N o z R
H Rº | or a pharmaceutically acceptable salt or solvate thereof; in which R is -Co-Cçalqu-C1-Cçealquila, -Co-Cçalqu-C1-Ceéhaloalkyl, -C1-Cçalg-O- Cir-Cealquila, -Ci-Cçéalqgu-S-C1-Cçéalquila, —-Cr-Cealqu-S-Ca -Cealqu-CO2H, -Cr Cçealqu-arila, -Cr-Cealqu-O-arila, -Cr-Cealqu-NH-arila, -Ci-Cealqu-S-arila, -Co- Cçalqu-heteroaryl, -C-Cçalqu- O-heteroaryl, -C7-Cçalqu-S-heteroaryl, -C, -Cçalqu- NH-heteroaryl, or -C (O) NH-aryl; Rº is -CiCçalguila, y -Cr-Céhaloalkyl, -C> -Cçéalenenila, or —Cx- Cçealquinila; R is H, haologenium, NH> 2, or -C1-Cçalquila; Rº is halo, -Ci-Ceéalquila, -C1-Céalg-O-C1-Ceéalquila, -NRRó ', -NHCONRÔ R º, -NHC (S) NRÓRÔ, -NH-O-Rº, or -NH-NRºRÔ;
R * is H, halo, -C1-Cálquila, -C1-Cehalogenoalkyl, -C2-Cealquenila, -C2- Cçealquinila, or -C1-Ceçalqu-OH; and Rº and Rô are each, independently, H, Ci-Cçalquila, or C1- Cçealqu-O-C1 -Cçalquila; or Rº and Rº, together with the atom to which they are attached, form a C3-Cç heterocycloalkyl ring.
47. The compound according to aspect 46, wherein R 'is -Cx-Calkyl-O-heteroaryl.
48. The compound according to aspect 47, wherein the -C1- Cçealqu-O-heteroaryl is ((2-amino-3-bromoquinolin-7-yl) oxy) methyl, (((2-amino-3 - chloroquinolin-7-yl) oxy) methyl, ((2-amino-3-fluoroquinolin-7-yl) oxy) methyl, ((2 - ((cyclopropylmethyl) amino) quinolin-7-yl) oxy) methyl, ( (2- (methylamino)) quinolin-7-yl) oxy) methyl, ((2-aminoquinolin-7-yl) oxy) methyl, ((indol-6-yl) oxy) methyl, 2- (methoxyamino) quinolin- 7-I) oxy) methyl, ((quinolin-7-yl) oxy) methyl, or ((((indazol-6-yl) oxy) methyl).
49. The compound according to aspect 46, wherein R1 is -C1- Cçalg-S-heteroaryl.
50. The compound according to aspect 49, wherein the -C1- Cçealqu-S-heteroaryl is ((2-amino-3-bromoquinolin-7-yl) thio) methyl, ((2-amino-3- chloroquinolin-7-yl) thio) methyl, ((2-amino-3-fluoroquinolin-7-yl) thio) methyl, ((2- ((cyclopropylmethyl) amino) quinolin-7-yl) thio) methyl, (( 2- (methylamino) quinolin-7-yl) thio) methyl, ((2-aminoquinolin-7-yl) thio) methyl, ((indol-6-yl) thio) methyl, (2- (methoxyamino) quinolin-7 -yl) thio) methyl, ((quinolin-7-yl) thio) methyl, ((3-methylimidazo [1,2-a] pyridin-7-yl) thio) methyl or ((indazol-6-yl) thio ) methyl.
51. The compound according to aspect 46, wherein R1 is -C1- Cçealqu-NH-heteroaryl.
52. The compound according to aspect 51, wherein the -C1- Cçealqu-NH-heteroaryl is ((2-amino-3-bromoquinolin-7-yl) amino) methyl, ((2-amino-3- chloroquinolin-7-yl) amino) methyl, ((2-amino-3-fluoroquinolin-7-yl) amino) methyl, ((2 - ((cyclopropylmethyl) amino) quinolin-7-yl) amino) methyl, (( 2- (methylamino) quinolin-7-yl) amino) methyl, ((2-aminoquinolin-7-yl) amino) methyl, ((indol-6-yl) amino) methyl, (2- (methoxyamino) quinolin-7 -yl) amino) methyl, ((quinolin-7-yl) amino) methyl, ((3-methylimidazo [1,2-a] pyridin-7-yl) amino) methyl or ((indazol-6-yl) amino ) methyl.
53. The compound according to aspect 46, wherein R1 is -Co- Ceal-alkyl-heteroaryl.
54. The compound according to aspect 53, in which the -Co-Cealealqu-heteroaria is 2- (2-amino-3-bromoquinolin-7-yl) ethyl, 2- (2-amino-3-chloroquinolin- 7-yl) ethyl, 2- (2-amino-3-fluoroquinolin-7-yl) ethyl, 2- (2 - ((cyclopropylmethyl) amino) quinolin-7-yl) ethyl, 2- (2- (methylamino) quinolin-7-yl) ethyl, 2- (2-aminoquinolin-7-yl) ethyl, ((indol-6-yl) ethyl, or ((indazol-6-yl) ethyl).
55. The compound according to aspect 46, wherein R 'is -Cx-Ceal-alkyl-S-alkyl.
56. The compound, according to aspect 55, in the -C1-Cecealqu-S-C1-Crealquila is -CH2-S-CH3.
57. The compound according to aspect 46, wherein R 'is --C1- Cçalg-S-C1-Cçalg-CO, H.
58. The compound, according to aspect 57, in the -C1-Cçéalg-S- C1-Cçalg-CO2H is - CH2-S-CH2CH2CH (NH2) -CO> 2H.
59. The compound according to aspect 46, wherein R 'is -Cx- Cealeal-O-C1-Calkyl.
60. The compound, according to aspect 59, in the -C1-Cealqu-O-C1-Crealquila is -CH2-0-CH3.
61. The compound according to aspect 46, wherein R 'is -C1- Cçealqu-O-aryl.
62. The compound, according to aspect 61, in the C1-Cçalqu-O- aryl is -CH, 7-O-phenyl, -CH, -O-difluorophenyl, -CH2-0-3,4-difluorophenyl, -CH2-0-4- chlorophenyl, -CH2-0-3-chloro-4-fluorophenyl, -CH2-0-4-chloro-3-fluorophenyl, -CH7-O- dichlorophenyl, -CH72-0-3,4 -dichlorophenyl, -CH2-0-3-methyl-4-chlorophenyl, -CH2-0-3-fluoro-4-trifluoromethylphenyl, -CH2-0-3- (aminomethyl) phenyl, or -CH2-0-3- ( urea) phenyl.
63. The compound according to aspect 46, wherein R * is -Co- Cealeal-C1-Cehaloalkyl.
64. The compound, according to aspect 63, in the -Co-Ceal-Ci-Cehaloalkyl is -CH, 2-CI.
65. The compound according to aspect 46, where R 'is -Cx- Ceal-alkyl-aryl.
66. The compound according to aspect 65, in which -C1-Cçealq-aryl is -CH, -difluorophenyl, -CH2-3,4-difluorophenyl, a -CH, 2-4-chlorophenyl, -CH, - 3-chloro-4-fluorophenyl, -CH2-4-chloro-3-fluorophenyl, -CH-dichlorophenyl, -CH2-3,4-dichlorophenyl, -CH2 -3-methyl-4-chlorophenyl, -CH2 -3-fluoro -4-trifluoromethylphenyl, benzo [d] [1,3] dioxazol-5-ylmethyl, -CH (OH) -4-chlorophenyl, -CH (OH) -3,4-dichlorophenyl, - CH (OH) -3, 4-difluorophenyl, -CH (OH) -3-fluoro-4-chlorophenyl, -CH (OH) -3-chloro-4-fluorophenyl, - “- CH (OH) -3-methyl4-chlorophenyl -CH (OH) -3-fluoro-4-trifluoromethylphenyl, -CH (OH) -benzo [d] [1,3] dioxazol-5-yl, -CH (F) -4-chlorophenyl, - CH (F) -3,4- dichlorophenyl, -CH (F) - 3,4-difluorophenyl, -CH (F) -3-fluoro-4-chlorophenyl, -CH (F) - 3-chloro-4-fluorophenyl, -CH (F) -3- methyl-4-chlorophenyl, -CH (F) -3-fluoro-4-trifluoromethylphenyl, -CH (F) -benzo [d] [1,3] dioxazol-5-yl, -CH (NH> 2) -4 -chlorophenyl, -CH (NH> 2, -3,4-dichlorophenyl, -CH (NH2) -3,4-difluorophenyl, -CH (NH) -3-fluoro-4-chlorine phenyl, -CH (NH2) -3-chloro-4-fluorophenyl, -CH (NH 2) -3-methyl-4-chlorophenyl, -CH (NH 2) -3-fluoro-4-trifluoromethylphenyl, -CH (NH 2) -benzo [d] [1,3] dioxazol-5-yl,
- CH (Me) -4-chlorophenyl, -CH (Me) -3,4-dichlorophenyl, -CH (Me) -3,4-difluorophenyl, - CH (Me) -3-fluoro-4-chlorophenyl, -CH (Me) -3-chloro-4-fluorophenyl, -CH (Me) -3-methyl-4-chlorophenyl, -CH (Me) -3-fluoro-4-trifluoromethylphenyl, -CH (Me) -benzo [d] [1,3] dioxazol-5-yl, -C (Me) (OH) -4-chlorophenyl, -C (Me) (OH) -3,4-dichlorophenyl, -C (Me) (OH) -3, 4-difluorophenyl, -C (Me) (OH) -3-fluoro-4-chlorophenyl, -C (Me) (OH) -3-chloro-4-fluorophenyl, -CH (Me) (OH) -3-methyl - 4-chlorophenyl, -C (Me) (OH) -benzo [d] [1,3] dioxazol-5-yl or -CH (Me) (OH) -3-fluoro-4-trifluoromethylphenyl.
67. The compound according to aspect 66, wherein the -C1- Cçealg-aryl is -CH (OH) -3,4-dichlorophenyl.
68. The compound according to aspect 46, wherein R 'is - C (O) NH-aryl.
69. The compound according to aspect 46, wherein the - C (O) NH-aryl is 3- (aminomethyl) phenyl-NH-C (O) -.
70. The compound, according to any one of aspects 1 to 69, in which R is C1-Cçalquila, preferably methyl.
71. The compound, according to any one of aspects 1 to 69, in which R is -C7-Cehaloalkyl, preferably -CF3.
72. The compound, according to any of aspects 46 to 69, in which R is -C,> - Cçalquenila, preferably vinyl.
73. The compound, according to any of aspects 46 to 69, in which R is -C2-Cçalquinyl, preferably ethynyl.
74. The compound, according to any of aspects 46 to 73, in which R is H.
75. The compound, according to any of aspects 1 to 74, in which Rº is C1-Cçalquila, preferably methyl.
76. The compound, according to any of aspects 1 to 74, where Rº is -Ci-Cçéalg-O-C -Cçalquila.
77. The compound, according to any of aspects 46 to 74, in which Rº is chlorine, fluorine, bromine, or iodine.
78. The compound, according to any of aspects 46 to 74, in which Rº is NRÓRó, in which Rº and RÔ are both preferably H.
79. The compound, according to any of aspects 1 to 74, where Rº is -NHCONR "R", where Rº and RÔ are both preferably - Cir-Crealquila.
80. The compound, according to any of aspects 46 to 74, where Rº is -NHC (S) NRÓRº.
81. The compound, according to any one of aspects 1 to 74, where Rº is -NH-O-R $, where R $ is preferably -C 7-Cçalquila.
82. The compound, according to any of aspects 1 to 74, in which Rº is -NH-NR6Rg ', in which Rk and Rº are both preferably -C 1- Cçalguila or in which R $ is preferably -Ci-Cçalguila and Rº is preferably H.
83. The compound, according to any of aspects 46 to 82, where Rº is H.
84. The compound according to any one of aspects 46 to 82, wherein R * is halo, preferably fluorine.
85. The compound of any one of aspects 1 to 82, where R * is —C1-Cçalquila.
86. The compound of any one of aspects 1 to 82, in which R is -C1-Cehaloalkyl.
87. The compound, according to any of aspects 46 to 82, wherein R * is -C> -Céalkenyl, preferably vinyl.
88. The compound according to any one of aspects 46 to 82, wherein R * is -C, -Calquinyl, preferably ethynyl.
89. The compound, according to any one of aspects 1 to 82, in which R is -C1-Cçéalg-OH.
90. A pharmaceutical composition comprising a compound defined according to any of aspects 46 to 89, and a pharmaceutically acceptable excipient.
91. The method for inhibiting an arginine methyltransferase 5 (PRMTB5) enzyme, characterized by the fact that it comprises: contacting the PRMT5 enzyme with an effective amount of a compound defined according to any of aspects 46 to 89.
92. The method of treating a disease or disorder associated with aberrant PRMT5 activity in a subject that comprises administering to the subject, a compound defined according to any of aspects 46 to 89.
93. The method according to aspect 92, in which the disease or disorder associated with aberrant PRMT5 activity is breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, cervical cancer, cervical cancer, leukemia, such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myeloid leukemia (AML), leukemia, chronic myeloid leukemia (AML), leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid cancer or hemoglobinopathies such as b-thalassemia and sickle cell disease (SCD).
94. A compound of Formula |:
Rô À, Ho e | the EnaR
OA o N o z Ri
H Rº | or a pharmaceutically acceptable salt or solvate thereof; where R * is -Co-Cealqu-C1-Cçealquila, -Co-Cçalqu-C1-Cehaloalkyl, -C1-Cealg-O- Ci-Cealquila, -Ci-Cçalqgu-S-Ci-Cçéalquila, —-Cr-Céçalqu -S-Ci-Céalqu-CO2H, -Cyr- Cçalqu-arila, -Cr-Cçalqu-O-arila, -Cr-Cçalqu-NH-arila, -Ci-Céçalqu-S-arila, -Co- Cçealqu-heteroarila, -C1-Cealqu-O-heteroaryl, -C1-Cçalqu-S-heteroaryl, -C1-Cealqu-NH-heteroaryl, or -C (O) NH-aryl; Rº is -CiCçalguila, y -Cr-Céhaloalkyl, -C> -Cçéalenenila, or —Cx- Cçealquinila; R is H, haologen, NH>, or -C1-Cecealkyl; Rº * is halo, -CiCçalguilay -Ci-Ceéalk-O-Ci-Cçalquila, -NRÓRO, - NHCONR "RS, -NHC (S) NRÓRS, -NH-OR $, or -NH-NRÓRº; R * is H, halo, -C7-Cálquila, -C-Céhalogenoalkyl, -C2-Cçéalquenila, -C> 2- Cçealquinila, or -c 1 .c 6 alkyl-OH; and Rº and RÔ are each, independently, H, C1-Cçéalquila , or Cr Cçealqu-O-C1-Cçalquila, or Rº and Rº, together with the atom to which they are attached, form a C3-Cç heterocycloalkyl ring.
95. The compound according to aspect 94, in which R 'is -C1- alkyl-O-heteroaryl.
96. The compound according to aspect 95, wherein the -Cx- Cealeal-O-heteroaryl is ((2-amino-3-bromoquinolin-7-yl) oxy) methyl, (((2-amino-3 - chloroquinolin-7-yl) oxy) methyl, ((2-amino-3-fluoroquinolin-7-yl) oxy) methyl, ((2 - ((cyclopropylmethyl) amino) quinolin-7-yl) oxy) methyl, ( (2- (methylamino)) quinolin-7-yl) oxy) methyl, ((2-aminoquinolin-7-yl) oxy) methyl, ((indol-6-yl) oxy) methyl, 2- (methoxyamino) quinolin- 7-I) oxy) methyl, ((quinolin-7-yl) oxy) methyl, or ((((indazol-6-yl) oxy) methyl).
97. The compound according to aspect 94, wherein R1 is -C1- Cçalg-S-heteroaryl.
98. The compound according to aspect 97, wherein the -Cx-Cealeal-S-heteroaryl is ((2-amino-3-bromoquinolin-7-yl) thio) methyl, ((2-amino-3- chloroquinolin-7-yl) thio) methyl, ((2-amino-3-fluoroquinolin-7-yl) thio) methyl, ((2- ((cyclopropylmethyl) amino) quinolin-7-yl) thio) methyl, (( 2- (methylamino) quinolin-7-yl) thio) methyl, ((2-aminoquinolin-7-yl) thio) methyl, ((indol-6-yl) thio) methyl, (2- (methoxyamino) quinolin-7 -yl) thio) methyl, ((quinolin-7-yl) thio) methyl, ((3-methylimidazo [1,2-a] pyridin-7-yl) thio) methyl or ((indazol-6-yl) thio ) methyl.
99. The compound according to aspect 94, wherein R, is -Cx- Cealeal-NH-heteroaryl.
100. The compound according to aspect 99, wherein the -C1- Cçealqu-NH-heteroaryl is ((2-amino-3-bromoquinolin-7-yl) amino) methyl, ((2-amino-3- chloroquinolin-7-yl) amino) methyl, ((2-amino-3-fluoroquinolin-7-yl) amino) methyl, ((2 - ((cyclopropylmethyl) amino) quinolin-7-yl) amino) methyl, (( 2- (methylamino) quinolin-7-yl) amino) methyl, ((2-aminoquinolin-7-yl) amino) methyl, ((indol-6-yl) amino) methyl, (2- (methoxyamino) quinolin-7 -yl) amino) methyl, ((quinolin-7-yl) amino) methyl, ((3-methylimidazo [1,2-a] pyridin-7-yl) amino) methyl or ((indazol-6-yl) amino ) methyl.
101. The compound according to aspect 94, wherein R1 is -Co- Cecealqu-heteroaryl.
102. The compound according to aspect 101, wherein the -C, - Cçealqu-heteroaria is 2- (2-amino-3-bromoquinolin-7-yl) ethyl, 2- (2-amino-3-chloroquinolin -7-yl) ethyl, 2- (2-amino-3-fluoroquinolin-7-yl) ethyl, 2- (2 - ((cyclopropylmethyl) amino) quinolin-7-yl) ethyl, 2- (2- (methylamino ) quinolin-7-yl) ethyl, 2- (2-aminoquinolin-7-yl) ethyl, ((indol-6-yl) ethyl, or ((indazol-6-yl) ethyl).
103. The compound according to aspect 94, wherein R 'is -Cx- Ceal-alkyl-S-alkyl.
104. The compound, according to aspect 103, in the -C1-Cecealqu-S-Ci-Cçalquila is -CH2-S-CH; 3.
105. The compound according to aspect 94, where R 'is --C1- Cçealg-S-C1-Cealg-CO> 2H.
106. The compound, according to aspect 105, in the -C1-Cçalg-S-C1-Cçalg-CO2H is - CH2-S-CH2CH2CH (NH2) -CO> 2H.
107. The compound according to aspect 94, wherein R 'is -Cx- Cealeal-O-C1-Calkyl.
108. The compound, according to aspect 107, in the -C1-Cecealqu- O-Ci-Cçalquila is -CH2-0-CH3.
109. The compound, according to aspect 94, wherein R 'is -Cx- Cealeal-O-aryl.
110. The compound according to aspect 109 in which the C1-Cçealqu-O-aryl is -CH7-O-phenyl, -CH7-O-difluorophenyl, -C H2-0-3,4-difluorophenyl, -CH2 -0-4- chlorophenyl, -CH2-0-3-chloro-4-fluorophenyl, -CH2-0-4-chloro-3-fluorophenyl, -CH7-O-dichlorophenyl, -CH72-0-3,4-dichlorophenyl , -CH2-0-3-methyl-4-chlorophenyl, -CH2-0-3-fluoro-4-trifluoromethylphenyl, -CH2-0-3- (aminomethyl) phenyl, or -CH2-0-3- (urea) phenyl.
111. The compound according to aspect 94, where R * is -Co- Cealeal-C1-Cehaloalkyl.
112. The compound, according to aspect 111, in the -Co-Cçalqu-Ci-Cehaloalkyl is -CH, 2-CI.
113. The compound according to aspect 94, wherein R 'is -Cx- Ceal-alkyl-aryl.
114. The compound according to aspect 113, wherein -C1-Cçalq- aryl is -CH, -difluorophenyl, -CH2-3,4-difluorophenyl, a -CH, 2-4-chlorophenyl, -CH, - 3-chloro-4-fluorophenyl, -CH2-4-chloro-3-fluorophenyl, -CH-dichlorophenyl, -CH2-3,4-dichlorophenyl, -CH2 -3-methyl-4-chlorophenyl, -CH2 -3-fluoro -4-trifluoromethylphenyl, benzo [d] [1,3] dioxazol-5-ylmethyl, -CH (OH) -4-chlorophenyl, -CH (OH) -3,4-dichlorophenyl, - CH (OH) -3, 4-difluorophenyl, -CH (OH) -3-fluoro-4-chlorophenyl, -CH (OH) -3-chloro-4-fluorophenyl, - “- CH (OH) -3-methyl4-chlorophenyl -CH (OH) -3-fluoro-4-trifluoromethylphenyl, -CH (OH) -benzo [d] [1,3] dioxazol-5-yl, -CH (F) -4-chlorophenyl, - CH (F) -3,4- dichlorophenyl, -CH (F) - 3,4-difluorophenyl, -CH (F) -3-fluoro-4-chlorophenyl, -CH (F) - 3-chloro-4-fluorophenyl, -CH (F) -3- methyl-4-chlorophenyl, -CH (F) -3-fluoro-4-trifluoromethylphenyl, -CH (F) -benzo [d] [1,3] dioxazol-5-yl, -CH (NH 2) -4- chlorophenyl, -CH (NH2 -3,4-dichlorophenyl, -CH (NH2) -3,4-difluorophenyl, -CH (NH 2) -3-fluoro-4-chlor ofenyl, -CH (NH 2) -3-chloro-4-fluorophenyl, -CH (NH 2) -3-methyl-4-chlorophenyl, -CH (NH 2) -3-fluoro-4-trifluoromethylphenyl, -CH ( NH 2) -benzo [d] [1,3] dioxazol-5-yl, - CH (Me) -4-chlorophenyl, -CH (Me) -3,4-dichlorophenyl, -CH (Me) -3,4 -difluorophenyl, - CH (Me) -3-fluoro-4-chlorophenyl, -CH (Me) -3-chloro-4-fluorophenyl, -CH (Me) -3-methyl-4-chlorophenyl, -CH (Me) -3-fluoro-4-trifluoromethylphenyl, -CH (Me) -benzo [d] [1,3] dioxazol-5-yl, -C (Me) (OH) -4-chlorophenyl, -C (Me) (OH ) -3,4-dichlorophenyl, -C (Me) (OH) -3,4 -difluorophenyl, -C (Me) (OH) -3-fluoro-4-chlorophenyl, -C (Me) (OH) -3 - chloro-4-fluorophenyl, -CH (Me) (OH) -3-methyl-4-chlorophenyl, -C (Me) (OH) -benzo [d] [1,3] dioxazol-5-yl or -CH (Me) (OH) -3-fluoro-4-trifluoromethylphenyl.
115. The compound according to aspect 114, wherein the -C1- Cçealg-aryl is -CH (OH) -3,4-dichlorophenyl.
116. The compound according to aspect 94, wherein R 'is - C (O) NH-aryl.
117. The compound according to aspect 94, wherein the - C (O) NH-aryl is 3- (aminomethyl) phenyl-NH-C (O) -.
118. The compound, according to any one of aspects 1 to 117, in which R is C1-Cçéalkyl, preferably methyl.
119. The compound according to any one of aspects 1 to 117, wherein R 'is -C1-Cehaloalkyl, preferably -CF3.
120. The compound, according to any of aspects 94 to 117, in which R is -C> -Calquenyl, preferably vinyl.
121. The compound, according to any of aspects 94 to 117, in which R is -C> -Calquinyl, preferably ethynyl.
122. The compound, according to any of aspects 94 to 121, in which R is H.
123. The compound, according to any of aspects 1 to 122, in which Rº is C1-Cçéalkyl, preferably methyl.
124. The compound, according to any one of aspects 1 to 122, where Rº is -C7-Cçéalg-O-C-Cçalquila.
125. The compound, according to any of aspects 94 to 122, in which Rº is chlorine, fluorine, bromine, or iodine.
126. The compound, according to any of aspects 94 to 122, where Rº is -NRÓRS ', where Rº and RÔ are both preferably H.
127. The compound, according to any of aspects 1 to 122, where Rº is -NHCONRÓR ', where Rº and R $ are both preferably - Ci-Cçalquila.
128. The compound, according to any of aspects 94 to 122, where Rº is -NHC (S) NR6Rº.
129. The compound according to any one of aspects 1 to 122, where Rº is -NH-O-R6, where R6 is preferably -C -Cálquila.
130. The compound, according to any of aspects 1 to 122, in which Rº is -NH-NR6R6 ', where R6 and Rº are both preferably - CrCealguila or where * 6 is preferably -Ci-Céalguila and RÔ is preferably H.
131. The compound, according to any of aspects 94 to 130, in which D H.
132. The compound according to any one of aspects 94 to 130, wherein R * is halo, preferably fluorine.
133. The compound of any one of aspects 1 to 130, in which R is —C1-Cçalquila.
134. The compound of any one of aspects 1 to 130, where R is -C1-Cehaloalkyl.
135. The compound according to any one of aspects 94 to 37, wherein R * is -C> -Cçéalkenyl, preferably vinyl.
136. The compound according to any one of aspects 94 to 130, wherein R * is -C7-C-alkealquinyl, preferably ethynyl.
137. The compound, according to any one of aspects 1 to 130, in which R is -C1-Cçéalg-OH.
138. A pharmaceutical composition comprising a compound defined according to any one of aspects 94 to 137, and a pharmaceutically acceptable excipient.
139. The method for inhibiting a protein enzyme arginine methyltransferase 5 (PRMTB5), characterized by the fact that it comprises:
contacting the PRMT5 enzyme with an effective amount of a compound defined according to any of aspects 94 to 137.
140. The method of treating a disease or disorder associated with aberrant PRMT5 activity in a subject comprising administering to the subject, a compound defined in accordance with any of aspects 94 to 137.
141. The method according to aspect 140, in which the disease or disorder associated with aberrant PRMT5 activity is breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, cervical cancer, cervical cancer, leukemia, such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myeloid leukemia (AML), leukemia, chronic myeloid leukemia (AML), leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid cancer or hemoglobinopathies such as b-thalassemia and sickle cell disease (SCD).
142. The method according to aspect 14 or aspect 141, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more other agents.

权利要求:
Claims (27)
[1]
1. Compound of Formula |: Rô a SA s ve
NAAS ss N o 7 Ri
H Rº | or a pharmaceutically acceptable salt, solvate or isotopic variant thereof; Characterized by the fact that R * is -Co-Cealqu-C1-Cçealquila, -Co-Cçalqu-C1-Cehaloalkila, -C1-Cealg-O- Ci-Cealquila, -Ci-Cçalqgu-S-Ci-Cçéalquila, —- Cr-Céçalqu-S-Ci-Céalqu-CO2H, -Cyr- Cçalqu-arila, -Cr-Cçalqu-O-arila, -Cr-Cçalqu-NH-arila, -Ci-Céçalqu-S-arila, -Co- Cçealqu -heteroaryl, -C1-Cealqu-O-heteroaryl, -C1-Cçalqu-S-heteroaryl, -C1-Cealqu-NH-heteroaryl, or -C (O) NH-aryl; Rº is -CiCçalguila, y -Cr-Céhaloalkyl, -C> -Cçéalenenila, or —Cx- Cçealquinila; R is H, haologen, NH>, or -C1-Cecealkyl; Rº is H, halo, -Ci-Cçéalkyl, -Ci-Cçalg-O-Ci-Céalquila, -NRÓRS, - NHCONR "RS, -NHC (S) NRÓRS, -NH-OR $, or -NH-NRºRô; * is H, halo, -Cr-Créalkyl, -Ci-Céhaloalkyl, -C2> -Cçalquenila, -C7- Cçalquinila, or -Cr-Cçalqu-OH; and
Rº and RÔ are each, independently, H, C1-Cçalquila, or C1- Cçealqu-O-C1-Cçalquila; or Rº and RÔ, together with the atom to which they are attached, form a C3-Cç heterocycloalkyl ring.
[2]
A compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized by the fact that R * is -C1- alkyl-O-heteroaryl.
[3]
A compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that the -Cx- Cçealqu-O-heteroaryl is ((2-amino-3-bromoquinolin-7-yl) oxy) methylA, (((2-amino-3-chloroquinolin-7-yl) oxy) methyl, ((2-amino-3-fluoroquinolin-7-yl) oxy) methyl, ((2- ((cyclopropylmethyl) amino) quinolin- 7-yl) oxy) methyl, ((2- (methylamino) quinolin-7-yl) oxy) methyl, ((2-aminoquinolin-7-yl) oxy) methyl, ((indol-6-yl) oxy) methyl , (2- (methoxyamino) quinolin-7-yl) oxy) methyl, ((quinolin-7-yl) oxy) methyl, ((3-methylimidazo [1,2-a] pyridin-7-yl) oxy) methyl or ((indazol-6-yl) oxy) methyl.
[4]
A compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized by the fact that R 'is -C1- Calkylalkyl aryl.
[5]
A compound according to claim 4, or a pharmaceutically acceptable salt thereof, characterized in that the -Cx- Cçealg-aryl is -CH, 2-difluorophenyl, -CH2-3,4-difluorophenyl, -CH2 -4-chlorophenyl, -CH2-3- chloro-4-fluorophenyl, - -CH, 2-4-chloro-3-fluorophenyl, - -CH7-dichlorophenyl, - -CH2-3,4- dichlorophenyl, -CH7-3 -methyl-4-chlorophenyl, -CH72-3-fluoro-4-trifluoromethylphenyl, benzo [d] [1,3Idioxazol-5-ylmethyl, -CH2- (4-chloro-2- (hydroxymethyl) phenyl), -CH2- (4-chloro- 2- (aminomethyl) phenyl), -CH7- (4-chloro-2 - ((methylamino) methyl) phenyl), -CH2-4-trifluoromethylphenyl, -CH7-4- (trifluoromethoxy) phenyl, - CH72-4-fluoro-3-trifluoromethylphenyl, -CH7-4-isopropylphenyl, -CH (OH) -4-chlorophenyl, -CH (0H) -3,4-
dichlorophenyl, -CH (OH) -3,4-difluorophenyl, -CH (OH) -3-fluoro-4-chlorophenyl, -CH (OH) - 3-chloro-4-fluorophenyl, -CH (OH) -3- methyl-4-chlorophenyl, -CH (OH) -3-fluoro-4-trifluoromethylphenyl, - -CH (OH) -benzo [d] [1,3] dioxazol-5-yl, - -CH (OH) - ( 4-chloro-2- (hydroxymethyl) phenyl), -CH (OH) - (4-chloro-2- (aminomethyl) phenyl), -CH (OH) - (4-chloro-2- ((methylamino) methyl) phenyl), -CH (OH) -4-trifluoromethylphenyl, -CH (OOH) -4- (trifluoromethoxy) phenyl, -CH (O0H) -4-fluoro-3-trifluoromethylphenyl, -CH (O0H) -4- isopropylphenyl, -CH (F) -4-chlorophenyl, - -CH (F) -3,4-dichlorophenyl, - -CH (F) -3,4- difluorophenyl, -CH (F) -3-fluoro-4-chlorophenyl, -CH (F) - 3-chloro-4-fluorophenyl, -CH (F) - 3-methyl-4-chlorophenyl, -CH (F) -3-fluoro-4-trifluoromethylphenyl, -CH (F) - benzo [ d] [1,3Idioxazol-5-yl, -CH (F) - (4-chloro-2- (hydroxymethyl) phenyl), -CH (F) - (4-chloro-2- (aminomethyl) phenyl), - CH (F) - (4-chloro-2 - ((methylamino) methyl) phenyl), -CH (F) -4-trifluoromethylphenyl, -CH (F) -4- (trifluoromethoxy) phenyl, -CH (F) - 4-fluoro-3-trifluoromethylphenyl, -CH (F) -4-isopropylphenyl la, -CH (NH2) -4-chlorophenyl, -CH (NH2) -3,4- dichlorophenyl, - -CH (NH2) -3,4-difluorophenyl, - -CH (NH2) -3-fluoro-4- chlorophenyl, —- CH (NH2) -3-chloro-4-fluorophenyl, -CH (NH2) -3-methyl-4-chlorophenyl, -CH (NH2) -3-fluoro- 4-trifluoromethylphenyl, -CH (NH2) -benzo [d] [1,3Idioxazol-5-yl, -CH (NH2) - (4-chloro-2- (hydroxymethyl) phenyl), -CH (NH2) - (4-chloro-2- (aminomethyl) phenyl ), -CH (NH2) - (4-chloro-2- ((methylamino) methyl) phenyl), -CH (NH2) -4-trifluoromethylphenyl, -CH (NH2) -4- (trifluorometho xi) phenyl, -CH (NH2) -4-fluoro-3-trifluoromethylphenyl, -CH (NH2) -4-isopropylphenyl, -CH (Me) -4-chlorophenyl, -CH (Me) -3,4-dichlorophenyl, -CH (Me) - 3,4- difluorophenyl, -CH (Me) -3-fluoro-4-chlorophenyl, -CH (Me) -3-chloro-4-fluorophenyl, - CH (Me) -3-methyl-4-chlorophenyl, - - CH (Me) -3-fluoro-4-trifluoromethylphenyl, - -CH (Me) - benzo [d] [1,3Idioxazol-5-yl, -CH (Me) - (4-chloro-2- (hydroxymethyl) phenyl ), -CH (Me) - (4-chloro-2- (aminomethyl) phenyl), -CH (Me) - (4-chloro-2 - ((methylamino) methyl) phenyl), -CH (Me) - 4 -trifluoromethylphenyl, -CH (Me) -4- (trifluoromethoxyphenyl a, -CH (Me) -4-fluoro-3-trifluoromethylphenyl, -CH (Me) -4-isopropylphenyl, -C (Me) (0H) -4-chlorophenyl, - C (Me) (OOH) -3, 4-dichlorophenyl, -C (Me) (0H) -3,4-difluorophenyl, -C (Me) (OH) -3-fluoro-4-
chlorophenyl, -C (Me) (OH) -3-chloro-4-fluorophenyl, -C (Me) (OOH) -3-methyl-4-chlorophenyl, - C (Me) (OH) -benzo [d] [ 1.3] dioxazol-5-yl, —-C (Me) (OH) -3-fluoro-4-trifluoromethylphenyl, - C (Me) (OOH) - (4-chloro-2- (hydroxymethyl) phenyl), -C (Me) (OOH) - (4-chloro-2- (aminomethyl) phenyl), -C (Me) (OH) - (4-chloro-2 - ((methylamino) methyl) phenyl), -C ( Me) (OH) - 4-trifluoromethylphenyl, -C (Me) (OH) -4- (trifluoromethoxy) phenyl, -C (Me) (OOH) -4-fluoro-3-trifluoromethylphenyl, or -C (Me) ( OH) -4-isopropylphenyl.
[6]
A compound according to any one of claims 1a5, characterized by the fact that R is C1-Cçalquila, preferably methyl.
[7]
Compound according to any one of claims 1 to 6, characterized by the fact that R is H.
[8]
8. “Compound according to any one of claims 1 to 7, characterized by the fact that Rº is H.
[9]
9. “Compound according to any one of claims 1 to 7, characterized by the fact that Rº is C1-Cçalquila, preferably methyl.
[10]
10. A compound according to any one of claims 1 to 7, characterized by the fact that Rº is -NRºRº, where Rº and Rº are preferably H.
[11]
A compound according to any one of claims 1 to 7, characterized by the fact that Rº is -NH-O-R $, where Rº is preferably - Ci-Cçalquila.
[12]
12. A compound according to any one of claims 1 to 7, characterized by the fact that Rº is -NH-NRÓRÔ, where Rº and R $ are both preferably -C1-Cçsalquila or where Rº is preferably -Ci-Cçéalquila and RÔ is preferably H.
[13]
13. A compound according to any one of claims 1 to 12, characterized by the fact that Rº is H.
[14]
Compound according to any one of claims 1 to 12, characterized in that R * is halo, preferably fluorine.
[15]
15. Compound according to claim 1, characterized by the fact that said compound is a compound of the formula | -C or | -D of the formula: Ts Ze RO Õ »-, DA heteroaryl - - = / H (IC ), NS He Hr, RNA LE so / TEA RW aryl (1I-D), or a pharmaceutically acceptable salt, solvate or isotopic variant thereof, where Rº is -NRºRº, -NH-O-Ró or -NH-NRºRº ; R ÉHourF; Rº and RÔ are each, independently, H or C1-Cçalquila; heteroaryl is substituted quinolinylay, indolyl, substituted indolyl, indazolyl, substituted indazolyl, substituted imidazo [1,2-a] pyridinyl or imidazo [1,2-a] pyridinyl; and aryl is phenyl or substituted phenyl.
[16]
A compound according to claim 15, or a pharmaceutically acceptable salt thereof, characterized in that R ° is -NH>, -NH-OH, -NH-O-CH3 or -NH-NHCH ;.
[17]
17. A compound according to claim 15, or a pharmaceutically acceptable salt thereof, characterized by the fact that aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, -3-fluoro- 4-chlorophenyl, -3-chloro-4-fluorophenyl, -3-methyl-4-chlorophenyl, -3-fluoro-4-trifluoromethyl-phenyl or -4-fluoro-3-trifluoromethyl-phenyl.
[18]
18. A compound according to claim 15, or a pharmaceutically acceptable salt thereof, characterized by the fact that heteroaryl is quinolin-7-yl, (2-amino-3-bromoquinolin-7-yl), (2-amino -3-chloroquinolin-7-yl), (2-amino-3-fluoroquinolin-7-yl), (2- (methylamino) quinolin-7-yl), (2-aminoquinolin-7-yl), 2- ( methoxyamino) quinolin-7-yl (indol-6-yl), (indazol-6-yl) or (3-methylimidazo [1,2-a] pyridine-7yl).
[19]
19. A compound according to claim 15, or a pharmaceutically acceptable salt thereof, characterized in that said compound is (2R, 35, 4R, 5R) -5- (4-amino-7H-pyrrole [2 , 3-d] pyrimidin-7-yl) -2 - ((((2-aminoquinolin-7-yl) oxy) methyl) -3-methyltetrahydrofuran-3,4-diol; (2R, 3S, 4R, 5R) -5- (4-amino-5-fluoro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) - 2 - ((((2-aminoquinolin-7-yl ) oxy) methyl) -3-methyltetrahydrofuran-3,4-diol; (2R, 3S, 4R, 5R) -2 - ((((2-amino-3-bromoquinolin-7-yl) oxy) methyl) -5- (4-amino-7H-pyrrolo [2,3-d] pyrimidine -7-yl) -3-methyltetrahydrofuran-3,4-diol; (2R, 3S, 4R, 5R) -5- (4-amino-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -3-methyl-2- ((quinolin-7-yloxy) methyl) tetrahydrofuran-3,4-diol; (2R, 3S, 4R, 5R) -5- (4-amino-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -3-methyl-2- ((((3-methylimidazo [1,2 -a] pyridin-7-yl) oxy) methyl) tetrahydrofuran-3,4-diol;
(2R, 35, 4R, 5R) -5- (4-amino-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2 - ((R) - (4-chlorophenyl) (hydroxy) methyl ) -3-methyltetrahydrofuran-3,4-diol; (Z) -7 - (((2R, 3R, 45, 5R) -5 - ((R) - (4-chlorophenyl) (hydroxy) methyl) -3,4-dihydroxy-4-methyl-tetrahydrofuran-2-yl) - 3,7-dihydro-4H-pyrrolo [2,3-d] pyrimidin-4-one oxime; (2R, 35, 4R, 5R) -5- (4-amino-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2 - ((R) - (3,4-dichlorophenyl) (hydroxy ) methyl) -3-methyl-tetrahydrofuran-3,4-diol; (2R, 35, 4R, 5R) -5- (4-amino-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2 - ((R) - (4-chloro-3-methylphenyl) (hydroxy) methyl) -3-methyltetrahydrofuran-3,4-diol; (2R, 35, 4R, 5R) -5- (4-amino-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2 - ((R) - (4-fluoro-3- (trifluoromethyl )) phenyl) (hydroxy) methyl) -3-methyltetrahydrofuran-3,4-diol.
[20]
A compound according to claim 19, or a pharmaceutically acceptable salt thereof, characterized in that said compound is (2R, 3S, 4R, 5R) -5- (4-amino-7H-pyrrole [2 , 3-d] pyrimidin-7-yl) -2 - ((R) - (3,4-dichlorophenyl) (hydroxy) methyl) -3-methyltetrahydrofuran-3,4-diol.
[21]
21. Pharmaceutical composition characterized by the fact that it comprises a compound defined according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
[22]
22. Pharmaceutical composition according to claim 21, characterized in that the compound is (2R, 3S, 4R, 5R) -5- (4-amino-7H-pyrrolo [2,3-d] pyrimidin-7 -yl) -2 - ((R) - (3,4-dichlorophenyl) (hydroxy) methyl) -3-methyltetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt thereof.
[23]
23. Method for inhibiting an arginine methyltransferase 5 enzyme (PRMTS5), characterized in that it comprises: contacting the PRMT5 enzyme with an effective amount of a compound defined according to any one of claims 1 to 20, or a salt pharmaceutically acceptable product.
[24]
24. Method for treating a disease or disorder associated with aberrant PRMT5 activity in a subject characterized by the fact that it comprises administering to the subject, a compound defined according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.
[25]
25. Method according to claim 24, characterized in that the disease or disorder associated with aberrant PRMTS5 activity is breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, cancer uterine cancer, cervical cancer, cervical cancer, leukemia, such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myeloid leukemia (AML) chronic myeloid (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid cancer or hemoglobinopathies such as b-thalassemia and sickle cell disease (SCD).
[26]
26. Method according to claim 24 or claim 25, characterized in that the compound, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more other agents.
[27]
27. Method according to any of claims 23-26, characterized in that the compound is (2R, 3S, 4R, 5R) -5- (4-amino-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -2 - ((R) - (3,4-dichlorophenyl) (hydroxy) methyl) -3-methyltetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt thereof.

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法律状态:
2021-11-03| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US201762543141P| true| 2017-08-09|2017-08-09|

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US62/543,141|2017-08-09|

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US201862630581P| true| 2018-02-14|2018-02-14|

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US62/630,581|2018-02-14|

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US201862664442P| true| 2018-04-30|2018-04-30|

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US62/664,442|2018-04-30|

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PCT/US2018/046057|WO2019032859A1|2017-08-09|2018-08-09|Selective inhibitors of protein arginine methyltransferase 5 |

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